Enabling precision manufacturing of active pharmaceutical ingredients: workflow for seeded cooling continuous crystallisations

Continuous manufacturing is widely used for the production of commodity products. Currently, it is attracting increasing interest from the pharmaceutical industry and regulatory agencies as a means to provide a consistent supply of medicines. Crystallisation is a key operation in the isolation of the majority of pharmaceuticals and has been demonstrated in a continuous manner on a number of compounds using a range of processing technologies and scales. Whilst basic design principles for crystallisations and continuous processes are known, applying these in the context of rapid pharmaceutical process development with the associated constraints of speed to market and limited material availability is challenging. A systematic approach for continuous crystallisation process design is required to avoid the risk that decisions made on one aspect of the process conspire to make a later development step or steps, either for crystallisation or another unit operation, more difficult. In response to this industry challenge, an innovative system-wide approach to decision making has been developed to support rapid, systematic, and efficient continuous seeded cooling crystallisation process design. For continuous crystallisation, the goal is to develop and operate a robust, consistent process with tight control of particle attributes. Here, an innovative system-based workflow is presented that addresses this challenge. The aim, methodology, key decisions and output at each at stage are defined and a case study is presented demonstrating the successful application of the workflow for the rapid design of processes to produce kilo quantities of product with distinct, specified attributes suited to the pharmaceutical development environment. This work concludes with a vision for future applications of workflows in continuous manufacturing development to achieve rapid performance based design of pharmaceuticals

MI 48084-5353 (formerly Technical Fellow at General Motors Research), [email protected]. John R. Hauser is the Kirin Professor of Marketing

Abstract Morphing enables a website to learn (actively and near optimally) which banner advertisements to serve to each cognitive-style segment in order to maximize outcome measures such as click-through, brand consideration, or purchase. Consumer segments are identified automatically from consumers' clickstream choices. Morphing works best on high-traffic websites with tens of thousands of visitors because large samples are necessary to reach steady state optimally. This paper describes the first large-sample random-assignment field test of banner morphing -over 100,000 consumers viewing over 450,000 banners on CNET.com. (Previously published morphing evaluations evaluated morphing website characteristics and were based on predictive simulations using only priming-study data.) On relevant webpages, CNET's clickthrough rates almost double relative to control banners. We supplement the CNET field test with a focused experiment on an automotive information-and-recommendation website. The focused experiment replaces automated learning with a longitudinal design which tests the premise of morph-to-segment matching. Banners matched to cognitive styles, as well as the stage of the consumer's buying process and body-type preference, significantly increase click-through rates, brand consideration, and purchase likelihood relative to a control

MI 48084-5353 (formerly Technical Fellow at General Motors Research), [email protected]. John R. Hauser is the Kirin Professor of Marketing

Abstract Researchers and practitioners devote substantial effort to targeting banner advertisements, but less effort on how to communicate with consumers once targeted. Morphing enables a website to learn (actively and near optimally) which banner advertisements to serve to each cognitive-style segment in order to maximize click-through, brand consideration, and purchase. Cognitive-style segments are identified automatically from consumers' clickstreams. This paper describes the first large-sample random-assignment field-test of banner morphing -over 100,000 consumers viewing over 450,000 banners on CNET.com. On relevant webpages, CNET's click-through rates almost doubled relative to control banners. We supplement the CNET field test with a focused experiment on an automotive information-andrecommendation website. The focused experiment replaces automated learning with a longitudinal design to test the premise of morph-to-segment matching. Banners matched to cognitive styles, as well as the stage of the consumer's buying process and body-type preference, significantly increase click-through rates, brand consideration, and purchase likelihood relative to a control. Together the field and the focused experiments demonstrate that matching cognitive styles provide significant benefits above and beyond more-traditional targeting. Such improved banner effectiveness has strategic implications for allocations among media

Multiplicity dependence of charged-particle intra-jet properties in pp collisions at s\sqrt{s} = 13 TeV

International audienceThe first measurement of the multiplicity dependence of intra-jet properties of leading charged-particle jets in proton-proton (pp) collisions is reported. The mean charged-particle multiplicity and jet fragmentation distributions are measured in minimum-bias and high-multiplicity pp collisions at $\sqrt{s}$ = 13 TeV using the ALICE detector. Jets are reconstructed from charged particles produced in the midrapidity region ($|\eta| < 0.9$) using the sequential recombination anti-$k_{\rm T}$ algorithm with jet resolution parameters $R$ = 0.2, 0.3, and 0.4 for the transverse momentum ($p_{\rm T}$) interval 5$-$110 GeV/$c$. High-multiplicity events are selected by the forward V0 scintillator detectors. The mean charged-particle multiplicity inside the leading jet cone rises monotonically with increasing jet $p_{\rm T}$ in qualitative agreement with previous measurements at lower energies. The distributions of jet fragmentation functions $z^{\rm ch}$ and $\xi^{\rm ch}$ are measured for different jet-$p_{\rm T}$ intervals. Jet-$p_{\rm T}$ independent fragmentation of leading jets is observed for wider jets except at high- and low-$z^{\rm ch}$. The observed "hump-backed plateau" structure in the $\xi^{\rm ch}$ distribution indicates suppression of low-$p_{\rm T}$ particles. In high-multiplicity events, an enhancement of the fragmentation probability of low-$z^{\rm ch}$ particles accompanied by a suppression of high-$z^{\rm ch}$ particles is observed compared to minimum-bias events. This behavior becomes more prominent for low-$p_{\rm T}$ jets with larger jet radius. The results are compared with predictions of QCD-inspired event generators, PYTHIA 8 with Monash 2013 tune and EPOS LHC. It is found that PYTHIA 8 qualitatively reproduces the jet modification in high-multiplicity events except at high jet $p_{\rm T}$. These measurements provide important constraints to models of jet fragmentation

Observation of abnormal suppression of f0\mathrm{f}_{0}(980) production in p−-Pb collisions at sNN\sqrt{s_{\rm NN}} = 5.02 TeV

International audienceThe dependence of $\mathrm{f}_{0}$(980) production on the final-state charged-particle multiplicity in p$-$Pb collisions at $\sqrt{s_{\mathrm{NN}}} = 5.02$ TeV is reported. The production of $\mathrm{f}_{0}$(980) is measured with the ALICE detector via the $\mathrm{f}_0 (980) \rightarrow \pi^{+}\pi^{-}$ decay channel in a midrapidity region of $-0.5<y<0$. Particle yield ratios of $\mathrm{f}_{0}$(980) to $\pi$ and $\mathrm{K}^{*}$(892)$^{0}$ are found to be decreasing with increasing charged-particle multiplicity. The magnitude of the suppression of the $\mathrm{f}_{0}$(980)/$\pi$ and $\mathrm{f}_{0}$(980)/$\mathrm{K}^{*}$(892)$^{0}$ yield ratios is found to be dependent on the transverse momentum $p_{\mathrm{T}}$, suggesting different mechanisms responsible for the measured effects. Furthermore, the nuclear modification factor $Q_{\mathrm{pPb}}$ of $\mathrm{f}_{0}$(980) is measured in various multiplicity ranges. The $Q_{\mathrm{pPb}}$ shows a strong suppression of the $\mathrm{f}_{0}$(980) production in the $p_{\mathrm{T}}$ region up to about 4 GeV/$c$. The results on the particle yield ratios and $Q_{\mathrm{pPb}}$ for $\mathrm{f}_{0}$(980) may help to understand the late hadronic phase in p$-$Pb collisions and the nature of the internal structure of $\mathrm{f}_{0}$(980) particle

Common femtoscopic hadron-emission source in pp collisions at the LHC

International audienceThe femtoscopic study of pairs of identical pions is particularly suited to investigate the effective source function of particle emission, due to the resulting Bose-Einstein correlation signal. In small collision systems at the LHC, pp in particular, the majority of the pions are produced in resonance decays, which significantly affect the profile and size of the source. In this work, we explicitly model this effect in order to extract the primordial source in pp collisions at $\sqrt{s} = 13$ TeV from charged $\pi$-$\pi$ correlations measured by ALICE. We demonstrate that the assumption of a Gaussian primordial source is compatible with the data and that the effective source, resulting from modifications due to resonances, is approximately exponential, as found in previous measurements at the LHC. The universality of hadron emission in pp collisions is further investigated by applying the same methodology to characterize the primordial source of K-p pairs. The size of the primordial source is evaluated as a function of the transverse mass ($m_{\rm T}$) of the pairs, leading to the observation of a common scaling for both $\pi$-$\pi$ and K-p, suggesting a collective effect. Further, the present results are compatible with the $m_{\rm T}$ scaling of the p-p and p$-\Lambda$ primordial source measured by ALICE in high multiplicity pp collisions, providing compelling evidence for the presence of a common emission source for all hadrons in small collision systems at the LHC. This will allow the determination of the source function for any hadron--hadron pairs with high precision, granting access to the properties of the possible final-state interaction among pairs of less abundantly produced hadrons, such as strange or charmed particles

Measurement of Ωc0\Omega^0_{\rm c} baryon production and branching-fraction ratio BR(Ωc0→Ω−e+νe)/BR(Ωc0→Ω−π+){\rm BR(\Omega^0_c \rightarrow \Omega^- e^+\nu_e)} / {\rm BR(\Omega^0_c \rightarrow \Omega^- \pi^+)} in pp collisions at s\sqrt{s} = 13 TeV

International audienceThe inclusive production of the charm-strange baryon $\Omega^{0}_{\rm c}$ is measured for the first time via its semileptonic decay into $\Omega^{-}\rm e^{+}\nu_{e}$ at midrapidity ($|y|<0.8$) in proton$-$proton (pp) collisions at the centre-of-mass energy $\sqrt{s}=13$ TeV with the ALICE detector at the LHC. The transverse momentum ($p_{\rm T}$) differential cross section multiplied by the branching ratio is presented in the interval $2<p_{\rm T}<12~{\rm GeV}/c$. The branching-fraction ratio ${\rm BR}(\Omega^0_{\rm c} \rightarrow \Omega^{-}{\rm e}^{+}\nu_{\rm e})/ {\rm BR}(\Omega^0_{\rm c} \rightarrow \Omega^{-}{\pi}^{+})$ is measured to be 1.12 $\pm$ 0.22 (stat.) $\pm$ 0.27 (syst.). Comparisons with other experimental measurements, as well as with theoretical calculations, are presented

Exclusive four pion photoproduction in ultraperipheral Pb-Pb collisions at sNN=5.02\sqrt{s_{\rm NN}} = 5.02 TeV

International audienceThe intense photon fluxes from relativistic nuclei provide an opportunity to study photonuclear interactions in ultraperipheral collisions. The measurement of coherently photoproduced $\pi^+\pi^-\pi^+\pi^-$ final states in ultraperipheral Pb-Pb collisions at $\sqrt{s_{\mathrm{NN}}}=5.02$ TeV is presented for the first time. The cross section, d$\sigma$/d$y$, times the branching ratio ($\rho\rightarrow \pi^+ \pi^+ \pi^- \pi^-$) is found to be $47.8\pm2.3~\rm{(stat.)}\pm7.7~\rm{(syst.)}$ mb in the rapidity interval $|y| < 0.5$. The invariant mass distribution is not well described with a single Breit-Wigner resonance. The production of two interfering resonances, $\rho(1450)$ and $\rho(1700)$, provides a good description of the data. The values of the masses ($m$) and widths ($\Gamma$) of the resonances extracted from the fit are $m_{1}=1385\pm14~\rm{(stat.)}\pm3~\rm{(syst.)}$ MeV/$c^2$, $\Gamma_{1}=431\pm36~\rm{(stat.)}\pm82~\rm{(syst.)}$ MeV/$c^2$, $m_{2}=1663\pm13~\rm{(stat.)}\pm22~\rm{(syst.)}$ MeV/$c^2$ and $\Gamma_{2}=357 \pm31~\rm{(stat.)}\pm49~\rm{(syst.)}$ MeV/$c^2$, respectively. The measured cross sections times the branching ratios are compared to recent theoretical predictions

Systematic study of flow vector decorrelation in sNN=5.02\mathbf{\sqrt{\textit{s}_{_{\bf NN}}}=5.02} TeV Pb-Pb collisions

International audienceMeasurements of the $p_{\rm T}$-dependent flow vector fluctuations in Pb-Pb collisions at $\sqrt{s_{_{\rm NN}}} = 5.02~\mathrm{TeV}$ using azimuthal correlations with the ALICE experiment at the LHC are presented. A four-particle correlation approach [1] is used to quantify the effects of flow angle and magnitude fluctuations separately. This paper extends previous studies to additional centrality intervals and provides measurements of the $p_{\rm T}$-dependent flow vector fluctuations at $\sqrt{s_{_{\rm NN}}} = 5.02~\mathrm{TeV}$ with two-particle correlations. Significant $p_{\rm T}$-dependent fluctuations of the $\vec{V}_{2}$ flow vector in Pb-Pb collisions are found across different centrality ranges, with the largest fluctuations of up to $\sim$15% being present in the 5% most central collisions. In parallel, no evidence of significant $p_{\rm T}$-dependent fluctuations of $\vec{V}_{3}$ or $\vec{V}_{4}$ is found. Additionally, evidence of flow angle and magnitude fluctuations is observed with more than $5\sigma$ significance in central collisions. These observations in Pb-Pb collisions indicate where the classical picture of hydrodynamic modeling with a common symmetry plane breaks down. This has implications for hard probes at high $p_{\rm T}$, which might be biased by $p_{\rm T}$-dependent flow angle fluctuations of at least 23% in central collisions. Given the presented results, existing theoretical models should be re-examined to improve our understanding of initial conditions, quark--gluon plasma (QGP) properties, and the dynamic evolution of the created system

Measurement of (anti)alpha production in central Pb-Pb collisions at sNN\sqrt{s_{\rm NN}} = 5.02 TeV

International audienceIn this letter, measurements of (anti)alpha production in central (0$-$10%) Pb$-$Pb collisions at a center-of-mass energy per nucleon$-$nucleon pair of $\sqrt{s_{\rm NN}}$ = 5.02 TeV are presented, including the first measurement of an antialpha transverse-momentum spectrum. Owing to its large mass, (anti)alpha production yields and transverse-momentum spectra are of particular interest because they provide a stringent test of particle production models. The averaged antialpha and alpha spectrum is included into a common blast-wave fit with lighter particles, indicating that the (anti)alpha also participates in the collective expansion of the medium created in the collision. A blast-wave fit including only protons, (anti)alpha, and other light nuclei results in a similar flow velocity as the fit that includes all particles. A similar flow velocity, but a significantly larger kinetic freeze-out temperature is obtained when only protons and light nuclei are included in the fit. The coalescence parameter $B_4$ is well described by calculations from a statistical hadronization model but significantly underestimated by calculations assuming nucleus formation via coalescence of nucleons. Similarly, the (anti)alpha-to-proton ratio is well described by the statistical hadronization model. On the other hand, coalescence calculations including approaches with different implementations of the (anti)alpha substructure tend to underestimate the data