Drug substances decomposition products

Stability of a drug substance and product is monitored throughout the development and clinical phases. This monitoring requires stability-indicating assay methodology, and this is a subject that is separate from performulation per se. In most instances, the major, feasible decomposition products are identified early [51], and as such it is known if the pathways are hydrolytic, oxidative, or photochemical. 

The BP Commission can also call on expertise available in the British Pharmacopoeia laboratories situated in the premises of the Laboratory of the Government Chemist in West London. The BP laboratory carries out and validates assay procedures for the Commission and in addition, is responsible for the procurement, establishment, maintenance and sale of British Pharmacopoeia Chemical Reference Substances (BPCRS). These reference substances, as their name suggests, are authentic samples of a drug or decomposition product which are used as standards in a drug assay. The BP laboratory also fulfils an important forensic role in the control of counterfeit medicines. With the advent of the internet, the public can easily gain access to supplies of prescription-only medicines online. These medicines are often adulterated, contaminated or simply counterfeit, and comparison with authentic samples is necessary to ensure that the correct preparation is supplied. 

Since full analyses are carried out, a lot of data are generated. Every parameter is reviewed for trends that signal product aging or outright decomposition of the active principle this can be as cosmetic in nature as discoloration or as potentially hazardous as buildup of toxic derivatives. If the drug substance is an ester, for example, hydrolysis, particularly if moisture penetrates the primary packaging material, will decompose the compound into its acid and alcohol components. From a pharmaceutical or medical viewpoint, even if there is no toxicity issue involved, this will result in a loss of bioavailability. Even this is to be avoided because subpotency introduces therapeutic uncertainty and can go as far as lethal undertreatment. 

Water uptake causes a host of problems in drug products and the inactive and active ingredients contained in them. Moisture uptake has been shown to be an important factor in the decomposition of drug substances [1-8]. Moisture has also been shown to change surface properties of solids [9,10], alter flow characteristics of powders [11,12], and affect the compaction properties of solids [13]. This chapter discusses various mathematical models that can be used to describe moisture uptake by deliquescent materials. 

Impurities in drug substances and drug products continue to be a source of great concern, discussion, debate, and research. " These concerns and debates typically center on the potential safety risks associated with impurities due to contamination and the setting of acceptance criteria. However, the bulk of the work being performed in the pharmaceutical industry, with respect to impurities, is focused on the isolation, identification, qualification and quantification of impurities that are found as a result of the manufacturing process or through chemical decomposition. On the... 

Degradation products are those compounds produced through the chemical or thermal decomposition of the analyte. Container/closure adducts are generally the result of an interaction between a drug substance or intermediate with the container/closure material or extracta-bles from these materials. 

Stress testing is conducted to provide data on forced decomposition products and decomposition mechanisms for the drug substance. 

Characterization of Impurities and Decomposition Products in Bulk Drug Substances... 

Even if the same drug substance HPLC method is used for the drug product, forced decomposition studies must be performed again for the drug product to confirm the resolution of potential degradation products from the API. In addition, forced decomposition studies must also be performed for different dosage forms (capsule, tablet, suspension, injectable, etc.) of the same drug substance. 

In a report by Thoma and Kerker (95), the effects of irradiation time and absolute radiation dose on the decomposition rates and photoproducts of betametha-zone valerate chloramphenicol, molsidomine, metronidazole, and indomethacin were studied. Their results show that substances sensitive to UV radiation, such as the above-listed five drugs, despite their instability in sunlight, have little or no decomposition upon exposure to irradiation from tubular fluorescent lamps at an irradiation intensity of 79 W/m. In addition, for those compounds that did degrade, they noted differences in the quantitative relationships of the decomposition products as well as their decomposition rates. The tubular fluorescent lamps used were found to be unsuitable for simulation of direct daylight. 

Degradation products The compounds produced as a result of decomposition of the material of interest or API are often called degradation products (or degradants). It is necessary to be concerned with these products as well as those brought about by degradation of other compounds that may also be present as impurities in the drug substance. 

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