Many proteins are unstable in solution and must be formulated in the solid state. This has led to an increase in the use of lyophilized dosage forms. Lyophilization is a complicated processing method consisting of three major steps: freezing, primary drying, and secondary drying. This can lead to several formulation stability challenges including changes in ionization within the matrix, phase separation of the protein drug from added stabilizers, sufficient mobility within the system for movement of reactive species and protein side chains, and crystallization of excipients upon storage. Solid-State Nuclear Magnetic Resonance Spectroscopy (SSNMR) is used to characterize many important properties of lyophilized formulations including crystalline vs. amorphous content, polymorphic form, ionization profile, interaction between formulation components with domain sizes, and mobility within the cake matrix. In order to study ionization changes in lyophilized solids, SSNMR and UV/Vis Diffuse Reflectance spectroscopy were used. 13C-labeled fumaric, succinic, and butyric acids were added to formulations at various pH levels, and were used to quantify change in the ionization of the matrix by monitoring the ionization ratios of the carboxylic acid peaks using SSNMR. pH indicators were also added to the formulations and their ionization ratio was determined using UV/Visible Diffuse Reflectance Spectroscopy. The ionization profile in the solid state was compared with that in solution before lyophilization. A rank ordering of ionization shift was made in pharmaceutically relevant buffers. SSNMR proton relaxation times (1H T1 and 1H T1rho) for each formulation component can be compared to determine homogeneity within the lyophilized matrix. The concept of spin diffusion is used in order to determine the length scale on which the components are either homogeneous or phase separated. The domain size is typically 20-50 nm or 2-10 nm for 1H T1 and 1H T1rho, respectively. PVP and dextran polymers were phase separated on both domains for physical mixtures and lyophilized mixtures. BSA and lysozyme were both lyophilized with formulations containing sucrose, trehalose, or mannitol as the stabilizer. Mannitol crystallized, and the relaxation times showed phase separation. Sucrose and trehalose both formed homogeneous systems at both length scales when formulated in a 1:1 ratio with BSA or lysozyme. Aspartame was shown to be phase separated from trehalose. The SSNMR proton relaxation times were also used to measure the local mobility in the lyophilized matrix, as a timescale of picoseconds to nanoseconds is associated with the 1H T1 relaxation time. Mobility was monitored in formulations containing a fixed amount of sucrose and mannitol, but with a variable amount of an IgG2 protein. The 1H T1 relaxation times decreased as protein content increased. The formulations with the highest relaxation time (lowest mobility), was the most stable in accelerated temperature conditions as monitored by size exclusion chromatography and capillary isoelectric focusing. This method can be used to rank order the most stable formulations at time-zero. Anti-plasticization was also studied by formulating sorbitol in various ratios with trehalose. The 1H T1 relaxation times increased with increasing sorbitol content, while the glass transition temperature decreased. Sorbitol and trehalose glasses were also exposed to different temperature storage conditions. Sorbitol appears to promote aging, as the formulations with higher sorbitol content showed larger increases in proton relaxation time.

In dem vorliegenden paper wird die Position begründet, dass die Regulierungsstrukturen des deutschen öffentlichen Verkehrs reformiert werden müssen, wenn die Aufgabenträger und Unternehmen in die Lage versetzt werden sollen, den zukünftigen Herausforderungen der sich verstärkenden regionalen Disparitäten begegnen zu können: Schrumpfende Städte und dünn besiedelte ländliche Gebiete benötigen andere Mobilitätslösungen als Ballungsräume. Allerdings behindern die bestehenden finanziellen und rechtlichen Rahmenbedingungen des öffentlichen Verkehrs die Entwicklung bedarfsgerechter lokaler Mobilitätskonzepte. Gleichzeitig wird auf diese Weise der Status quo – die kostenträchtigen und unattraktiven Standardleistungen – konserviert. In einem ersten Schritt werden die Ergebnisse der Analyse verschiedener Fallstudien von Gebieten und Städten dargestellt, die mit Prozessen des Bevölkerungsschwunds konfrontiert werden. Die hier ausgewählten Fallbeispiele aus Ostdeutschland werden als exemplarisch für einen generellen Trend betrachtet; diese Vorgehensweise wird durch die entsprechenden demografischen Prognosen gedeckt: Eine rasant ansteigende Zahl von Gebieten und Städten wird in den nächsten 30 Jahren mit der hohen Herausforderung konfrontiert werden, Schrumpfungsprozesse zu bewältigen. Die Analyse konzentriert sich auf zwei Fragestellungen: (1) Auf welche Weise beeinflusst eine schrumpfende Bevölkerung den öffentlichen Verkehr? (2) Welche Maßnahmen und Strategien wurden bislang von den betroffenen Aufgabenträgern und Unternehmen realisiert, um mit den neuen Herausforderungen umzugehen? Die Fallstudien zeigen, dass sich die Schrumpfungsprozesse je nach den spezifischen regionalen Bedingungen unterscheiden. In einem zweiten Schritt wird die zentrale These des papers diskutiert: Entsprechend der Analyse der finanziellen und rechtlichen Rahmenbedingungen wird argumentiert, dass diese Strukturen eine lokale Entwicklung adäquater Strategien des downsizing verhindern. Im dritten Schritt wird dargelegt, auf welche Weise die Rahmenbedingungen des öffentlichen Verkehrs reformiert werden müssen, um vermehrt Lösungen für regionale Anpassungen zu befördern. Solche Gebiete, die absehbar am stärksten durch den Bevölkerungsschwund betroffen sein werden, sollten als offizielle Experimentierräume ausgewiesen werden, so dass hier neue Mobilitätslösungen nicht auf die sonst üblichen (rechtlichen) Barrieren stoßen. So könnten etwa Gutschein-basierte Lösungen erprobt werden, die bisherige Lösungen für die öffentliche Bezuschussung ablösen könnten. / The paper argues that the governance of public transport in Germany needs to be reformed if transport authorities and transport companies want to address the challenges posed by increasing regional disparities: „Shrinking cities“ and thinly populated rural areas need mobility solution different from those in agglomerations; yet, the structures of funding and regulating public transport discourage the development of „custom-made“ local mobility concepts while preserving the status-quo of a costly and unattractive standard service. In a first step we will present our analysis of several case studies of districts and cities confronted with a process of „population drain“. Backed by the relevant demographic projections we take the eastern German cases chosen here as exemplary for a general trend: Coping with „shrinking processes“ will be a major challenge for an increasing number of districts and cities in the next 30 years. The analysis focuses on two questions: (1) How does a decreasing population affect public transport? (2) Which measures and strategies have local transport authorities and companies so far adopted to cope with the new challenges? The case studies show that shrinking-patterns differ according to a set of regional characteristics. In a second step the central hypothesis will be discussed: analysing the regulation and financing tools which form the governance regime of public transport we argue that these structures inhibit the local development of adequate „downsizing“ strategies. In a third step we suggest how governance structures must be reformed to make them fit for more regional diversity. Those areas most severely affected by a „population drain“ should be declared „governance laboratories“ where experiments with new mobility solutions are granted special tolerance and regulatory innovations such as a voucher-based system of public funding may be tested.

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