Selective manipulation of crystal shape by combined crystallization, milling, and dissolution stages - An approach for robust process design

Solid formulations are nowadays extremely important in everyday life, especially concerning food and pharmaceutical products. Particularly in the latter case, the size and shape of the active pharmaceutical ingredients play a major role in determining their properties, both in terms of processability and bioavailability. For this reason, the interest in the crystallization community is driven nowadays more and more towards the identification of solutions to control the morphology of the particles during crystallization processes. Currently, the use of additives and antisolvents, as well as milling the particles after crystallization, are techniques commonly applied in industry. In order to avoid chemical impurities and fines in the final products, processes involving temperature cycles, eventually combined with a feedback controller, have also proved to be an interesting alternative. In this work, a new technique based on the combination of crystallization, milling and dissolution is proposed to control the shape of crystals. The crystallization stage is used to recover the solute from solution, while milling is used to break particles lengthwise, therefore reducing their length and leading to more equant shaped crystals. The fines formed during rupture are subsequently removed by dissolving them and the three stages are repeated for the desired number of cycles. The approach used for a successful process design is thoroughly explained. First of all, it is necessary to develop devices to reliably and accurately measure multidimensional particle size and shape distributions. This is fundamental for a precise characterization of the basic phenomena occurring during the different stages. To this aim, the flow-through cell, an in-house built device, is used to monitor and measure populations of crystals and characterize them in terms of length and width; on top of that, a hot-stage microscope is used to investigate phenomena at the single particle scale. The experimental observation is used to develop a mathematical model, based on population balance equations. This model allows to describe phenomena typically occurring during crystallization processes, such as breakage and nucleation, hence allowing for an accurate prediction of experimental outcomes. The mathematical model developed proves to be a reliable tool for the investigation of the feasibility of the proposed process. After the identification of process variables, particular focus is placed on the effect of the amount of mass dissolved, the milling intensity and the number of cycles performed, by considering and comparing both average properties and the whole particle size and shape distributions. A parametric analysis is used to identify general process trends and possible tradeoffs, as well as close-to-optimality conditions. To conclude, a comparison with a single crystallization stage and cooling crystallization followed by milling is carried out, highlighting benefits and limitations of the new process on the alternatives proposed

Combined imaging and chromatic confocal microscopy technique to characterize size and shape of ensembles of cuboidal particles

The presence of needle- and plate-like particles has detrimental consequences on their downstream processing in the fine chemicals sector. Therefore, the ability to accurately characterize the particle size and shape is essential to quantify and predict their impact on the product processability. Nonetheless, tools to characterize both the size and shape of ensembles of cuboidal particles are seldom available. The overarching goal of this work is to provide a fast and accurate offline size and shape characterization tool. To this aim, we have designed and experimentally validated a combined imaging and chromatic confocal microscopy technique. We propose two modes of operation: one that facilitates the accurate 3D reconstruction of particles; and the other that facilitates their rapid characterization. We validate the performance of our technique using a commercial technique. We show that our technique can accurately characterize thousands of particles, making it a valuable addition to existing process analytical technology

Atom Strapdown: Toward Integrated Quantum Inertial Navigation Systems

We present an alternative technique for estimating the response of a cold atom interferometer (CAI). Using data from a conventional inertial measurement unit (IMU) and common strapdown terminology, the position of the atom wave packet is tracked in a newly introduced sensor frame, enabling hybridization of both systems in terms of acceleration and angular rate measurements. The sensor frame allows for an easier mathematical description of the CAI measurement and integration into higher-level navigation systems. The dynamic terms resulting from the transformation of the IMU frame into the CAI sensor frame are evaluated in simulations. The implementation of the method as a prediction model in an extended Kalman filter is explained and demonstrated in realistic simulations, showing improvements of over two orders of magnitude with respect to the conventional IMU strapdown solution. Finally, the implications of these findings for future hybrid quantum navigation systems are discussed

Crystal size, shape, and conformational changes drive both the disappearance and reappearance of ritonavir polymorphs in the mill.

Organic compounds can crystallize in different forms known as polymorphs. Discovery and control of polymorphism is crucial to the pharmaceutical industry since different polymorphs can have significantly different physical properties which impacts their utilization in drug delivery. Certain polymorphs have been reported to 'disappear' from the physical world, irreversibly converting to new ones. These unwanted polymorph conversions, initially prevented by slow nucleation kinetics, are eventually observed driven by significant gains in thermodynamic stabilities. The most infamous of these cases is that of the HIV drug ritonavir (RVR): Once its reluctant form was unwillingly nucleated for the first time, its desired form could no longer be produced with the same manufacturing process. Here we show that RVR's extraordinary disappearing polymorph as well as its reluctant form can be consistently produced by ball-milling under different environmental conditions. We demonstrate that the significant difference in stability between its polymorphs can be changed and reversed in the mill-a process we show is driven by crystal size as well as crystal shape and conformational effects. We also show that those effects can be controlled through careful design of milling conditions since they dictate the kinetics of crystal breakage, dissolution, and growth processes that eventually lead to steady-state crystal sizes and shapes in the mill. This work highlights the huge potential of mechanochemistry in polymorph discovery of forms initially difficult to nucleate, recovery of disappearing polymorphs, and polymorph control of complex flexible drug compounds such as RVR

All-optical matter-wave lens using time-averaged potentials

The precision of matter-wave sensors benefits from interrogating large-particle-number atomic ensembles at high cycle rates. Quantum-degenerate gases with their low effective temperatures allow for constraining systematic errors towards highest accuracy, but their production by evaporative cooling is costly with regard to both atom number and cycle rate. In this work, we report on the creation of cold matter-waves using a crossed optical dipole trap and shaping them by means of an all-optical matter-wave lens. We demonstrate the trade off between lowering the residual kinetic energy and increasing the atom number by reducing the duration of evaporative cooling and estimate the corresponding performance gain in matter-wave sensors. Our method is implemented using time-averaged optical potentials and hence easily applicable in optical dipole trapping setups. © 2022, The Author(s)

Optomechanical resonator-enhanced atom interferometry

Matter-wave interferometry and spectroscopy of optomechanical resonators offer complementary advantages. Interferometry with cold atoms is employed for accurate and long-term stable measurements, yet it is challenged by its dynamic range and cyclic acquisition. Spectroscopy of optomechanical resonators features continuous signals with large dynamic range, however it is generally subject to drifts. In this work, we combine the advantages of both devices. Measuring the motion of a mirror and matter waves interferometrically with respect to a joint reference allows us to operate an atomic gravimeter in a seismically noisy environment otherwise inhibiting readout of its phase. Our method is applicable to a variety of quantum sensors and shows large potential for improvements of both elements by quantum engineering. © 2020, The Author(s)

QGyro : Schlussbericht zum Verbundvorhaben Quanten-Inertialsensorsystem (QGyro)

Das Verbundvorhaben QGyro (Quanten-Inertialsensorsystem) ist ein Teil der High-Tech-Strategie der Bundesregierung und erhält Finanzierung durch das Bundesministerium für Wirtschaft und Klimaschutz (BMWK) mit Unterstützung der Raumfahrtagentur am Deutschen Zentrum für Luft- und Raumfahrt DLR e.V. (Förderkennzeichen 50RK1957). Im Rahmen dieses Forschungsvorhabens wurden mithilfe der Quantentechnologie innovative Konzepte für die Navigation von Plattformen entwickelt. Das Hauptziel des Projekts ist die Untersuchung von Hybridansätzen zur Inertialsensorik, bei der Quantensensoren mit klassischen inertialen Messeinheiten miteinander kombiniert werden um Fehler in der Positionsbestimmung zu reduzieren. Ein Hauptaugenmerk lag auf der Entwicklung neuartiger Quantensensoren. Ein erster Ansatz war die Schaffung eines einachsigen, quantenbasierten Inertialsensors als Proof-of-Concept. Dies beinhaltet den Sensorkopf, aber auch die Perepherie, wie Lasersysteme und Elektronik. Darüber hinaus wurden Entwicklungen in Richtung von sechsachsigen quantenbasierten Intertialsensoren angestoßen und Realisierungskonzepte erarbeitet. Ein besonderer Fokus lag auf der Stabilisierung und aktiven Ausrichtung des entwickelten Messkopfes, was durch Simulationen und experimentelle Tests nachgewiesen werden konnte. Dies beinhaltete die Entwicklung eines Teststandes, die Erarbeitung eines Atom-StrapDown-Algorithmus zur Kombination von Quanten-Inertialsensoren und klassischer Inertialsensorik sowie die Umsetzung einer stabilisierten Plattform für den Sensorkopf. Die erfolgreiche Umsetzung wurde in enger Zusammenarbeit mit Forschungseinrichtungen an der Leibniz Universität Hannover (Institut für Erdmessung, Institut für Quantenoptik) sowie etablierten Unternehmen wie der iMAR GmbH erreicht. Das Projekt QGyro trägt dazu bei, die High-Tech-Strategie der Bundesregierung im Bereich der Quantentechnologie und Navigation voranzutreiben.The collaborative project QGyro (quantum inertial sensor system) is part of the German Federal Government’s High-Tech Strategy and receives funding from the German Federal Ministry of Economics and Climate Protection (BMWK) with support from the Space Agency at the German Aerospace Center DLR e.V. (funding code 50 RK 1957). This research project used quantum technology to develop innovative concepts for the navigation of kinematic platforms. The main goal of the project is to investigate hybrid approaches for inertial sensors, combining quantum technology with classical inertial measurement devices in order to reduce errors in positioning. A primary focus has been the development of novel quantum sensors. A first approach considered the creation of a single-axis, quantum-based inertial sensor as a proof-of-concept. This includes the sensor head, and also the peripherals, such as laser systems and electronics. Furthermore, developments towards a six-axis quantum-based inertial sensor were initiated and realization concepts were elaborated. Further focus was on the stabilization and active alignment of the developed sensing head. For this purpose, a stabilized platform was designed and built that can compensate linear accelerations during the measurement time of the quantum sensor. A so-called Atom Strapdown algorithm was designed and implemented for inertial navigation for the combination of quantum inertial sensors and classical inertial sensors. This algorithm has been tested, optimized and validated in extensive simulation studies. Moreover, a successful application of the algorithm to real data was achieved by emulating the CAI observations with a navigation-grade IMU during the generation of the hybrid scenario. Algorithms for determining the uncertainties of the atomic interferometer were further developed and validated on prototype measurement series. Successful implementation was achieved in close collaboration with research institutions at Leibniz Universität Hannover (Institute of Geodesy, Institute of Quantum Optics) as well as established companies such as iMAR GmbH. The QGyro project contributes to advancing the German government’s high-tech strategy in the field of quantum technology and navigation.Deutsche Raumfahrtagentur im Deutschen Zentrum für Luft- und Raumfahrt e.V./Systemuntersuchungen und Technologie für die Satellitennavigation/BMWK 50 RK 1957/E

A Dual Projection Imaging System to Characterize Crystallization Processes: Design and Applications

Crystallization is a separation process that has been practised and applied widely in fine chemical and pharmaceutical industries. In the majority of applications, it is used to obtain a high purity solid form, which often exhibits a distribution of sizes and shapes. Crystallization involves a number of fundamental phenomena -- often poorly understood -- like nucleation, growth, dissolution, agglomeration, to name a few. The lack of reliable monitoring tools and techniques inhibits attaining deeper insights into the mechanisms involved, which naturally affects the robust and optimal operation of these crystallization processes. Poor understanding coupled with stringent targets on the product quality for drugs in terms of purity, stability, and bioavailability, has attracted significant attention from both the academia and the industry. The work presented in this thesis led to improvements in the state-of-the-art imaging techniques for size and shape characterization of the solid phase in batch solution crystallization processes. Based on these improvements, studies making use of the shape information obtained from the imaging device were undertaken for several interesting and previously unexplored applications. The former point led to providing better characterization and understanding of the process from a macroscopic scale. While the latter point with the aid of the former led to several automated and controlled approaches to manipulate the size and shape of undesirable needle-like crystals to equant crystals. The key accomplishments of this thesis were • enhancements to the hardware of a stereoscopic imaging device and to the imaging analysis routines to classify crystals observed by the imaging device into five different shape classes and to obtain a three-dimensional reconstruction of these crystals. • assessing the reliability of commercial spectroscopic techniques to estimate solute concentration in batch crystallization processes and proposing a new approach based on volumetric reconstruction of crystals observed by the stereoscopic imaging device, to estimate the solute concentration. • transformation of needle-like crystals to more equant crystals in a multistage cyclic process consisting of wet milling, dissolution, and growth stages, exploiting the online monitoring capabilities of the imaging device and simple feedback control laws for the individual stages. To summarize, the results obtained certainly reinforce the potential and the competence of imaging tools to tackle a wide array of challenges faced by the crystallization community. Irrespective of the promising outcome, their potential pitfalls are definitely not overlooked and plausible proposals to overcome these are discussed diligently to assist future research on monitoring, on modeling and on control of crystallization processes

Material Screening for Gas Sensing using an Electronic Nose: Gas Sorption Thermodynamic and Kinetic Considerations

To detect multiple gases in a mixture, one must employ an electronic nose or sensor array, composed of several materials as a single material cannot resolve all the gases in a mixture accurately. Given the many candidate materials, choosing the right combination of materials to be used in an array is a challenging task. In a sensor whose sensing mechanism depends on a change in mass upon gas adsorption, both the equilibrium and kinetic characteristics of the gas-material system dictate the performance of the array. The overarching goal of this work is two-fold. First, we aim to highlight the impact of thermodynamic characteristics of gas-material combination on array performance and to develop a graphical approach to rapidly screen materials. Second, we aim to highlight the need to incorporate the gas sorption kinetic characteristics to provide an accurate picture of the performance of a sensor array. To address these goals, we have developed a computational test bench that incorporates a sensor model and a gas composition estimator. To provide a generic study, we have chosen, as candidate materials, hypothetical materials that exhibit equilibrium characteristics similar to metal organic frameworks (MOFs). Our computational studies led to key learnings, namely: (1) exploit the shape of the sensor response as a function of gas composition for material screening purposes for gravimetric arrays; (2) incorporate both equilibrium and kinetics for gas composition estimation in a dynamic system; and (3) engineer the array by accounting for the kinetics of the materials, the feed gas flow rate, and the size of the device