Stability toxic degradation products

While stability studies are carried out on foods, the study of stability in pharmaceuticals is even more vital because of the need to avoid potentially toxic degradation products. Accordingly stability studies in the development of formulations are very thorough. Several samples must be studied at each of a wide range of temperature, humidity and light conditions and samples are taken regularly at intervals over total times of up to two years. 

Unexpected problems with product stability e.g. the detection of toxic degradation products... 

The primary application of TGA is to characterise a materiaTs weight loss vs. time at a given temperature or within a certain temperature range. The thermo-analytical technique is used for the structural characterisation of homopolymers, copolymers, polymeric blends, composites and rubbers and finds application in the detection of monomeric residuals, solvents, additives, toxic degradation products, ash content, etc., and for measurements related to thermal stability, volatilisation and evaporation. In order to elucidate the stmcture of complex polymeric materials, it is important to separate the constituting components. This can be done in several ways, such as by admission of air after initial heating in inert atmosphere. 

Biodegradable poly(phosphoester-urethanes) containing bisglycophosphite as the chain extender were synthesized. Methylene bis-4-phenyl isocyanate (MDI) and toluene diisocyanate (TDI) were initially used as diisocyanates. Since there was a concern that the degradation products could be toxic, the ethyl 2,6-diisocyanatohexanoate (LDI) was synthesized and replaced the MDI (or TDI). The hydrolytic stability and solubility of these polymers were tested. Preliminary release studies of 5-fluorouracil from MDI based poly(phosphoester-urethane) and methotrexate from LDI based poly(phosphoester-urethane) are also reported. 

Another associated issue was the possibility of inactivating the LRES (lym-phoreticuloendothelial system). By analogy with other injectable systems, it could also be deduced that the injectable emulsion system needed to be sterile and apy-rogenic and free of acute or chronic toxicities from components or their associated degradation products. It also followed that the injectable system required to be stable, although how stability was to be determined and, more to the point, measured, has remained an issue to the present day. This is mainly because emulsions are thermodynamically unstable although their stability can be extended by formulation. As a result emulsion products are now available that are submicron in diameter, sterile, and stable for several years after preparation. In major part this has been due to the use of phospholipids as stabilizers and emulsifiers, in particular the mixed products identified as the lecithin of commerce. 

It is prudent to evaluate impurity peaks observed in a supplier s bulk substance and compare them with those observed in the drug product. The extent that the peaks differ may determine the need to obtain further information, including toxicity. Samples of impurities/degradation products methods should be appropriately validated by the ANDA sponsor for their sensitivities and specificities. It also is recommended that the sponsor of an ANDA set up and maintain a stability program for the bulk drug substance. 

Chemical Stability Chemical degradation of the drug includes reactions such as hydrolysis, dehydration, oxidation, photochemical degradation, or reaction with excipients. The constant presence of water and oxygen in our environment means that exposure to moisture or oxygen can affect the chemical stability of a compound. Chemical stability is very important, not only because a sufficient amount of the dmg is needed at the time of administration for therapeutic purposes, but also because chemical degradation products may adversely affect the properties of the formulated product and may even be toxic. 

Provisional RfDs and RfCs for 25 degradation products, impurities and stabilizers (Bausum, 1998) are listed in Table 5. These values can be compared with the estimated oral RfD for VX of 0.0006 qg/kg/day (Opresko et al., 1998). Where data were unavailable for a degradation product, but the mechanism of action for the chemical was the same or predicted to be the same as that of VX, the value for VX was assigned. Thus, although both EA 2192 and bis(,S, S-(diisopropylaminoethyl) methylphosphonodithi-olate are less toxic than VX, the conservative value of 0.0006 qg/kg/day value was proposed. Health-based soil screening levels for the parent compound range from 0.042 to 0.047 mg/kg of soil (US Army CHPPM, 1999). 

Alternatively, the container may contain an opacifying agent, e.g., titanium dioxide. The use of multilayered bags was demonstrated to inhibit photochemical decomposition of vitamin E in TPN fat emulsions (Allwood and Martin, 2000). PVC films discolor on irradiative exposure due to photochemical degradation of the polymer (Hollande and Laurent, 1997). Plastic containers for parenteral use may contain several additives, e.g., antioxidants, stabilizers, plasticizers, lubricants, impact modifiers, and coloring matter when justified and authorized. In an appendix, the European Pharmacopoeia presents a list of plastic additives that may be used (European Pharmacopoeia, 2002). The additives should not be extracted by the contents in such quantities as to alter efficacy or stability of the product or to present any risk of toxicity (European Pharmacopoeia, 2002). However, organic additives extracted in concentrations below the detection limits of the analytical methods authorized by the European Pharmacopoeia may be sufficient to initiate photosensitized reactions in the formulation. 

The most effective fluorous solvents are perfluorinated alkanes, perfluorinated dialkyl ethers, and perfluorinated trialkyl amines. Their remarkable chemical inertness, thermal stability, and nonflammability coupled with their unusual physical properties make them particularly attractive for catalyst immobilization. Furthermore, these materials are practically nontoxic by oral ingestion, inhalation, or intraperito-neal injection [7]. Although their thermal degradation can produce toxic decomposition products, such decomposition generally begins only at very high temperatures well above the thermal stability limits of most organometallic compounds. 

Characteristics - trapping efficiency - ease of separation from the final product - solubility in crude monomer, raw material and coproducts - thermal stability - volatility - degradability - toxicity - ease of handling - price - trapping effectiveness - color formation - solubility - ease of handling - ease of removal or ability to override - toxicity... 

This section presents information and data related to thermal stability of resins and basic properties as a function of temperature. Thermal stability of fluoropolymers has special importance because of the high processing temperatures required by these thermoplastics and the toxic and corrosive nature of their degradation products. Fluoroplastics have useful properties at temperature extremes above and below ambient conditions. 

The compatibility of a colorant is assessed not only on the basis of the ease with which it can be mixed with the base resin to form a homogeneous mass but also on the requirement that it neither degrades nor is degraded by the resin. In relation to product functional properties, incompatibihty of a colorant can affect mechanical properties, flame retardancy, weatherability, chemical and ultraviolet resistance, and heat stability of a resin through interaction of the colorant with the resin and its additives. Flame retardancy, for example, may impinge directly on the performance of a colorant. Pressure to produce materials with lower levels of toxic combustion products can involve organic fire retardant additives that interact with the colorant either to negate the effect of the additives or affect the color. 

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