Bulletin of the American Physical Society
2007 APS March Meeting
Volume 52, Number 1
Monday–Friday, March 5–9, 2007; Denver, Colorado
Session U5: Pharmaceutical Materials Science |
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Sponsoring Units: FIAP Chair: Peter Stephens, State University of New York at Stony Brook Room: Colorado Convention Center Korbel 1A-1B |
Thursday, March 8, 2007 8:00AM - 8:36AM |
U5.00001: Solid forms of pharmaceuticals and thermodynamic stability Invited Speaker: |
Thursday, March 8, 2007 8:36AM - 9:12AM |
U5.00002: Water and stability of pharmaceutical solids Invited Speaker: Solid pharmaceuticals are multi-component systems consisting of an active pharmaceutical ingredient (API) and inactive ingredients (excipients). Excipients may include inorganic salts (e.g., NaCl), carbohydrates (e.g., lactose), and polymers, to name a few, whereas APIs range from relatively simple molecules (e.g., aspirin) to proteins and olygonucleotides. Pharmaceutical solids could exist either as single-phase or heterophase systems. They also may have different extent of order, such as highly ordered crystalline phases, amorphous solids that are thermodynamically unstable but might be kinetically stable under the time frame of observation, and crystalline mesophases including liquid crystals. With all this diversity, there are common features for such systems, and two of them will be discussed in the presentation. (i) Requirements for chemical stability of pharmaceuticals are very strict. A very limited (e.g., less than 0.1{\%}) extent of conversion is allowed in these materials over the shelf life, i.e., during several years of storage at ambient and (sometimes) not fully controlled (e.g., a medicine cabinet in one's bathroom) conditions. (ii) All pharmaceutical solids contain some water, although its amount and physical state are highly variable and may change during manufacturing and shelf life. There are many challenging questions and issues associated with the ``Water and stability of pharmaceutical solids'' subject; some of them will be considered in the presentation: (i) What are the features of chemical reactivity of crystalline vs disordered systems? (ii) What is the role of water in solid state chemical reactivity of amorphous solids, e.g., water as plasticizer vs reactant vs reaction media? (iii) How homogeneous are pharmaceutical amorphous solid solutions, e.g., carbohydrate-water systems? (iv) What is the optimal water content? With water being the most common destabilizing factor, is ``the drier - the better'' always the case? [Preview Abstract] |
Thursday, March 8, 2007 9:12AM - 9:48AM |
U5.00003: Physical and Chemical Aspects of Pharmaceutical Solids: Fundamentals of Polymorphs, Hydrates and Solvates Invited Speaker: Crystal polymorphs are solid phases of a given compound resulting from the possibility of at least two different arrangements of the molecules of that compound in the solid state. Solvates form when the solvent is incorporated in the crystal structure of a compound; hydrates form when water is the solvent of crystallization. The potential effects of crystal polymorphism and hydration on the quality and performance of drug products is widely recognized by the pharmaceutical industry. Investigations of crystal polymorphism and hydration are usually conducted early in drug development to optimize the physical properties of a pharmaceutical solid. Although the thermodynamically most stable crystal form is generally selected for commercial development to mitigate the risk of undesired phase transformations, form selection oftentimes involves a compromise among different physical properties of various drug crystal forms. Controlling polymorph (or hydrate) appearance must be accomplished through careful evaluation of both thermodynamic (tendency toward the formation of more stable crystal forms) and kinetic parameters (which lead to the formation of metastable forms) in the crystallization process. In this presentation, fundamental aspects of polymorphs and solvates (hydrates) will be explored. Particular attention will be given to the structure and stability relationships between polymorphs and hydrates, kinetic vs. thermodynamic transitions, and the impact of polymorphism and hydration on the chemical and physical stability of an active pharmaceutical ingredient. [Preview Abstract] |
Thursday, March 8, 2007 9:48AM - 10:24AM |
U5.00004: Stability in Glassy Pharmaceuticals: The Role of Glass Dynamics Invited Speaker: Many pharmaceutical products, particularly freeze dried therapeutic proteins, are often produced in the glassy state. Stability or resistance to degradation is often a serious problem, and we find stability differences between formulations of similar composition often differ by an order of magnitude or more. We seek a better understanding of those factors that determine physical and chemical stability so that more stable products may be efficiently developed. Our hypothesis is that differences in dynamics in the glassy state are at least partially responsible for formulation specific stability behavior of materials stored well below their T$_{g}$'s. Various measures of dynamics or ``mobility'' are compared with stability data obtained by chemical assay (HPLC) of samples stored at various temperatures and for various times. While the different measures of mobility are often well correlated, there exist several examples where a trend in dynamics with some variable depends greatly on the measure of dynamics being used for analysis. Experimental stability data suggest stability and calorimetric relaxation dynamics, an indicator of mobility on a large length scale and long time scale, or ``global mobility'', are well coupled in many cases. We review data for physical stability in small molecule amorphous systems, chemical stability in cephalosporin antibiotics, dimer formation in small molecule systems, and both chemical decomposition and aggregation in proteins. We also find evidence that stability may be improved by annealing, presumably as a result of the decrease in free volume (as determined by high precision density measurements) and the corresponding decrease in ``global'' mobility as determined by TAM experiments. We conclude that glass dynamics is an important factor in determining stability, both chemical and physical, of small molecules and proteins in the amorphous solid state. However, the correlations are far from perfect, and it appears that due recognition of ``Fast Dynamics'' may be critical for our understanding, particularly for stability well below T$_{g}$. [Preview Abstract] |
Thursday, March 8, 2007 10:24AM - 11:00AM |
U5.00005: Cohesion, Cracking, Dilation, and Flow -- Rheological Behavior of Cohesive Pharmaceutical Powders Invited Speaker: Cohesive powders can be loosely defined as systems where the attractive forced between particles exceed the average particle weight. Cohesive powder flow is interesting from a wide range of reasons. Their main characteristic, intermittence, is evidenced both in the interruption of flow out of hoppers (a mundane issue causing great annoyance to industrial practitioners) and in the sudden avalanching of snow and dirt that has terrified and terrified mankind since the dawn of time. At the present time, our ability to predict either of these phenomena (and many more involving cohesive powders) is very limited, primarily due to an incomplete understanding of their constitutive behavior. To wit, consider just a simple fact: \textbf{\textit{a flowing powder never has constant density}}. Equations describing the relationship between velocity, shear, stress, and density are rudimentary at best. Computational and experimental approaches for characterizing flow behavior are in their infancy. In this talk, I will describe some recent progress achieved at Rutgers by our group. New instruments have been developed to determine simultaneously powder density and cohesive flow effects. Extensive measurements have been carried out focusing on pharmaceutical blends. These results have been used to fine-tune computational models that accurately predict dilation, flow in drums, and flow in hoppers. Impact of these observations for pharmaceutical manufacturing applications will be discussed in some detail. [Preview Abstract] |
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