Physical Instabilities

Physical instability is a phenomenon which is rarely encountered with small organic molecules but arises in peptides and proteins because of the many conditions under which 

Denaturation refers to a dismption of the tertiary and secondary structure of the protein molecule. The denaturation can be reversible or irreversible. Denaturation caused by, for example, an increase of temperature is said to be reversible if the native stmcture is regained on decreasing the temperature. Irreversible denamration implies that the unfolding process is such that the native structure cannot be regained simply by lowering the temperamre (although it may sometimes be possible to remrn the protein to its native state 

Two basic pathways have been observed for proteins during denaturation and folding. The simplest is a two-state model. If we refer to the native state as N and the unfolded, denatured state as D, we can write 

Once critical hydrophobic residues are exposed to solvents they can interact with other surfaces (containers or the air/water interface). The process may involve the formation of intermediate conformations (I) which may be stable and may self-associate during folding. The second general pathway for denaturation includes these stable intermediate species and may be written 

The equation shows the unfolding of a native protein to form an intermediate, I , which then unfolds to form other intermediates. If 

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Because the facilitated transport process employs a specific reactive carrier species, very high membrane selectivities can be achieved. These selectivities are often far higher than those achieved by other membrane processes. This one fact has maintained interest in facilitated transport since the 1970s, but the problems of the physical instability of the liquid membrane and the chemical instability of the carrier agent are yet to be overcome. 

A ubiquitous feature accompanying large deformations in inelastic materials is the appearance of various instabilities. For example, plastic deformation may lead to shear banding, and the development of damage frequently leads to the formation of fault zones. As remarked in Section 5.2.7, normality conditions derived from the work assumption may imply stability which is too strong for such cases. Physical instabilities are likely to be associated with loss of normality and violation of the work assumption. 

For decades the problem of stability has plagued colloid chemists and others engaged in the manufacture and use of dispersions. Only a determined practical approach to the solution of this problem has been responsible for the modest accumulation of theoretical knowledge in existence today. In the field of dispersions, for example, problems of physical instability have been solved for paints, pharmaceuticals, adhesives, asphalt, detergents, and commodities used in the graphic arts, in addition to the numerous successful encounters with instability (or sometimes with undesired stability) in the food industry. 

Four major phenomena are associated with the-physical instability of emulsions flocculation, creaming, coalescence, and breaking (Fig. 8) [144]. 

More subtle effects of preservatives on injectable formulations are possible. Formulation of insulin is an illustrative case study. Insulin is usually formulated as a multiple-dose vial, since individual dosage varies among patients. Preservation of zinc insulin with phenol causes physical instability of the suspension, whereas methyl-paraben does not. However, the presence of phenol is required for obtaining protamine insulin crystals [9]. 

If SLN are incorporated into vehicles, interactions with the vehicle constituents may induce physical instabilities such as dissolution or aggregation of lipid particles. Therefore, during storage, particle sizes and the solid character of the particles have to be followed. 

Organic acids produced by the organisms can cause a drop in the pH of a formulation, resulting in physical instability. These same organic acids, along with other metabolic byproducts of the microorganisms, can also impart unwanted odours and colours which alter the appearance and absorption of the paint. Incorporation of a preservative is recommended to prevent these problems from occurring. 

Physical instability of the dosage form tablets that disintegrate too readily creams or suspensions that separate and over- or undercompression of tablets leading to deviation from the required weight... 

Chowhan [9] defined different pathways of physical instability of tablet formulations. These physical paths may involve one or more complex physical processes, e.g. change in polymorphism, crystallization, vaporization and adsorption. These pathways and thus the physical tablet parameters, are influenced by different types of variables formulation variables (e.g. solubility and hygroscopicity), in-process variables (e.g. moisture content) and aging variables (e.g. temperature and relative humidity). 

For heat pumps based on flooded mine systems, where the heat abstracted is replenished seasonally by inputs from solar radiation and geothermal gradient, the longevity of the reservoir is, in principle, limitless. The sustainability of the operation will only be limited by the durability of the infrastructure (e.g., biofouling, clogging or physical instability of boreholes, longevity of collector coils). 

All proteins and peptides display chemical and physical instability that affects the way they are distributed and cleared in the body and their delivery to the site of action. Physical and chemical instability is affected by primary sequences and secondary and tertiary structures and the degree of glyco-sylation of protein. Chemical degradation of proteins and peptides involves deamidation, racemization, hydrolysis, oxidation, beta elimination, and disulfide exchange. Physical degradation of proteins involves denaturation and aggregation. 

Figure 5.10. Possible mechanisms of chemical and physical instability that influence biological activities of protein pharmaceuticals. (Adapted from Manning et al. [18])...

Physical stability. As indicated earlier, conventional emulsions are inherently unstable from a physical standpoint. Poor physical stability is ultimately exhibited by phase separation, which can be visually monitored. Certain properties of the emulsion will start to change long before this separation is visually apparent. An increase in particle size is particularly indicative of physical instability, since this monitors the coalescence or Locculation that is part of the process involved in ultimate phase separation. Increases in viscosity (due to Locculation) and changes in zeta potential (arising from a decrease in droplet surface area) are both indicative of poor physical stability. The presence of drug and cosolvents can potentially hasten the phase separation. 

Both chemical and physical stability must be assured in the development of solid dispersions. Since the drug is either molecularly dispersed or intimately mixed with the carrier, there is potential for greater chemical interaction between them. Any physical instability that leads to phase transformations may result in poor performance of dosage forms, including changes in dissolution rates and oral bioavailability. 

Degradation pathways for proteins can be separated into two distinct classes chemical and physical. Chemical instability is any process which involves modification of the protein by bond formation or cleavage. Physical instability refers to changes in the protein structure through denatur-ation, adsorption to surfaces, aggregation, and precipitation [15]. 

Instability of an emulsion may be physical or chemical in nature. Chemical instability, which results in an alteration in the chemical structure of the lipid molecules due to oxidation or hydrolysis (McClements, 1999), will not be considered in this chapter for more information, the reader is referred to Chapters 11 and 12. Physical instability results in an alteration in the spatial distribution or structural organization of the globules (i.e., the dispersed phase of the emulsion). A number of important mechanisms responsible for the physical instability of emulsions, as depicted in Figure 5.1, can be divided into two categories gravitational separation and droplet aggregation. 

Droplet aggregation is said to occur when droplets stay together for a time much longer than they would in the absence of colloidal interactions, (i.e., than can be accounted for by collisions due to Brownian motion) (Walstra, 2003). Mechanisms responsible for the physical instability of droplets through aggregation are flocculation, coalescence or partial coalescence. 

Agglomeration/ Subvisual and visual Particle denaturation potential. Also correlates to immunogenic potential. Indicator of physical instability. Also... 

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