Variance Change Point Detection Under a Smoothly-Changing Mean Trend with Application to Liver Procurement

<p>Literature on change point analysis mostly requires a sudden change in the data distribution, either in a few parameters or the distribution as a whole. We are interested in the scenario, where the variance of data may make a significant jump while the mean changes in a smooth fashion. The motivation is a liver procurement experiment monitoring organ surface temperature. Blindly applying the existing methods to the example can yield erroneous change point estimates since the smoothly changing mean violates the sudden-change assumption. We propose a penalized weighted least-squares approach with an iterative estimation procedure that integrates variance change point detection and smooth mean function estimation. The procedure starts with a consistent initial mean estimate ignoring the variance heterogeneity. Given the variance components the mean function is estimated by smoothing splines as the minimizer of the penalized weighted least squares. Given the mean function, we propose a likelihood ratio test statistic for identifying the variance change point. The null distribution of the test statistic is derived together with the rates of convergence of all the parameter estimates. Simulations show excellent performance of the proposed method. Application analysis offers numerical support to non invasive organ viability assessment by surface temperature monitoring. Supplementary materials for this article are available online.</p

Ultrasonic Irradiation and Seeding To Prevent Metastable Liquid–Liquid Phase Separation and Intensify Crystallization

During the crystallization of complex pharmaceutical molecules, a liquid–liquid phase (LLP) separation phenomenon may occur that could hinder crystallization processes and adversely affect the crystal quality and process robustness. In this study, the LLP separation behavior of a vanillin and water mixture was investigated using a hot-stage microscope and a cooling crystallization process. Thermodynamic stability of phases and the crystallization phase diagram including the metastable zone width, nucleation, and LLP separation were developed. The impact of ultrasound and seeding on LLP separation was investigated and used to optimize the crystallization process. Our results show that the LLP separation may exist in both the stable and metastable zones of the crystallization phase diagram. Ultrasound can effectively promote nucleation, narrow the metastable zone of LLP separation, and inhibit LLP separation within the concentration range of 3.8–4.8 g/100 g water. Moreover, ultrasonic crystallization was optimized to produce small, uniformly sized crystals in a reproducible manner, whereas seeding crystallization was able to grow larger crystals without obvious agglomeration. In the case of a vanillin aqueous solution, both the ultrasonic induced and seeding crystallization strategies were able to prevent LLP separation and improve process performance. These results would be of significant use in the crystallization of other pharmaceutical molecules in which LLP separation occurs

Motion-Based Multiple Object Tracking of Ultrasonic-Induced Nucleation: A Case Study of l‑Glutamic Acid

A robust nucleation tracking technology was proposed to track the nucleation process of l-glutamic acid in this study. A motion-based multiple object tracking (MMOT) model was introduced to crystallization, for the first time, to help to track the moving crystals. A waterproof microcamera combined with a home-designed vial adaptor was used to record the nucleation process video stream. Optimization of parameters in the MMOT model and a moving average (MA) based smoothing method helped to determine the starting point of nucleation. Results showed the newly developed technology performed better under the influence of ultrasonic irradiation, which disabled the use of focused beam reflection measurement (FBRM)

Enhancement of protein crystallization with the application of Taylor vortex and Poly(ionic liquid)s

With the increase demands for biopharmaceuticals, the development of efficient protein crystallization processes for manufacturing highly pure crystalline products has become critical for downstream biomanufacturing. This work focused on the combined effects of the uniform shear rate in a solution created by using the Taylor vortex and the macromolecular architecture of a solution developed using poly(ionic liquid)s during protein crystallization. The results were as follows: (1) the accelerated primary nucleation rate with a uniform shear force that was generated by the Taylor vortex; (2) the stability of the protein product prepared using the poly(ionic liquid)s was high in the crystallization solution; and (3) improved control of supersaturation of the polymer was achieved with the salting-out effect. The average crystal size in the control group was considerably lower than 1 μm with low quality (9.00 Å) and yield (56%) of crystals, but the average size of lysozyme crystals obtained using the Taylor vortex and poly(ionic liquid)s increased up to 5 μm with high quality (1.86 Å) of crystals and yield (86%). A higher diffraction resolution indicated a better ordered crystalline structure, demonstrating that the Taylor vortex and poly(ionic liquid)s are useful for improving the crystal quality

Solubility of Cefotaxime Sodium in Ethanol + Water Mixtures under Acetic Acid Conditions

Aimed at exploring the influence of acetic acid on crystallization thermodynamics of cefotaxime sodium (CTX), the solubility of CTX in ethanol + water mixtures under acetic acid conditions at various temperatures are measured by a gravimetrical method. Different from the solubility curve when acetic acid is absent, the solubility curves of CTX under acetic acid conditions have a maximum value. The maximum solubility drifts as temperature varies, which is related to the dielectric constants of solvent mixtures. A combination of the Jouyban–Acree model and Apelblat equation is used to correlate the solubility data, and the correlation precision is improved when compared with that of the Jouyban–Acree model. By using the Wilson model, the activity coefficients of CTX and the mixing Gibbs free energies, enthalpies, and entropies of CTX solution are also predicted. The data presented in this study explain why the crystallization of CTX in ethanol + water mixtures is difficult and are helpful for guiding the industrial reaction and crystallization process of CTX

Gelation Phenomenon during Antisolvent Crystallization of Cefotaxime Sodium

In this paper, gelation phenomenon during the crystallization process of cefotaxime sodium (CTX) is systematically studied. First, the gelation process is monitored using a nanoparticle size analyzer; the gel and xerogel are studied by different characterization tools to speculate the gelation mechanism. It is found that the gelation is driven by the crystallization of CTX and the nanoparticles act as gelators before they can be seen by the naked eye. Moreover, the solid-solution interfacial tension used to predict the rate of crystal growth is calculated using the induction periods and solvents are classified using the Hansen solubility parameters method, according to whether it can be gelated by CTX. It is shown that the strong polar interaction between solvent molecules and the carboxyl, amine, or acyl groups exposed on the CTX crystal surface is the key factor for gelation