Synthetic drug substances limits

Modern spectroscopy plays an important role in pharmaceutical analysis. Historically, spectroscopic techniques such as infrared (IR), nuclear magnetic resonance (NMR), and mass spectrometry (MS) were used primarily for characterization of drug substances and structure elucidation of synthetic impurities and degradation products. Because of the limitation in specificity (spectral and chemical interference) and sensitivity, spectroscopy alone has assumed a much less important role than chromatographic techniques in quantitative analytical applications. However, spectroscopy offers the significant advantages of simple sample preparation and expeditious operation. 

Chewing leaves of the khat shrub is practiced in parts of East Africa and the Arabian peninsula (Kalix 1988 Widler et al. 1994). Some estimate daily use at 5 million portions. Use in the West is less common, but has increased somewhat. More common in the United States has been use of the synthetic drug methcathinone (or "cat"), which is derived from khat alkaloids. Only the fresh khat leaves are pharmacologically active, so for some time use was limited to local areas that grew the plant. However, with air transportation, use has spread with emigrants in Europe and the United States. Because of its pharmacological similarities to amphetamine and its addictive properties, khat has been listed on Schedule I of the United Nations Convention on Psychotropic Substances. 

The profile of impurities in a new drug substance may change for a variety of reasons, such as process scale-up changes, synthetic route changes, and changes made to key intermediates. ICH decision trees help classify, qualify, and select limits for new molecular entities (NMEs). If an impurity exceeds the qualification threshold listed below in Table 3 (ICFI Q3A(R)), studies are needed to qualify that impurity in drug substances. 

Examination of the synthetic route used in production allows for the prediction of potential residual synthetic impurities present in the drug substance. The API structure allows for the postulation of degradation pathways via hydrolytic, oxidative, catalytic, and other mechanisms. Both of these evaluations serve to facilitate the interpretation of (subsequent) identification tests. An examination of the physicochemical properties also allows for the rational establishment of method screening experiments by precluding certain conditions. For example, the use of normal-phase HPLC will be eliminated if the API is a salt or shows limited solubility in nonpolar organic solvents. Similarly, if the API (or suspected related substances) has no significant chromophore above 250 nm, the use of tetrahydrofuran (THE) and other solvents as mobile-phase components is severely limited. For compounds with an ionizable group, variation of pH will have considerable influence on elution behavior and can be exploited to optimize the selectivity of a reversed-phase separation. 

Among the related substances in many antibiotics are various structurally related components in the drug substance, the composite mixture of which is obtained in the synthetic or semisynthetic scheme and which gives rise to the drug efficacy. Control of the relative content of components is therefore necessary for these drugs. Test specification limits for the components are normally stated in terms of area percent of each, as maximum, minimum or a range of values for each or for the sums of several components. The types of components seen in these antibiotics were studied as impurities in the semisynthetic antibiotic clarithromycin, where detection limits of 0.1% w/w were found. Normalization factors were determined for each of 15 known related substances using ratios of the slope of linear calibrations for each substance to that for the reference impurity. 

Amphetamines (speed sulph, sulphate, uppers, wake-ups, billy whizz, whizz, whites, base) are synthetic stimulants which as medicines have been formed into a variety of tablets. Their current medical use is very limited and in fact only dexamphetamine sulphate, Dexedrine, is now available for use solely in the treatment of narcolepsy. The only other amphetamine available for medical use is methylphenidate (Ritalin) for the treatment of attention deficit syndrome in children. As a street drug, amphetamine usually comes as a white, grey, yellowish or pinky powder. The purity rate of street powders is less than 10%, the rest being made up of milder stimulants such as caffeine, other drugs such as paracetamol or substances like glucose, dried baby milk, flour or talcum powder. 

Many synthetic substances to be used in solid dosage form are too limited in solubility to be therapeutically effective. The desirable solubility for an oral solid is suggested to be more than 1 mg/ml (0.1%). To increase solubility, a weak basic drug such as an amine may react with respective mineral acids to form salts, that is, hydrochloride (more than 40% of the salt marketed), sulfate, or phosphate. For an amine with two functional groups, a mono- or dihydrochloride salt may be formed, depending on the condition and amount of hydrochloric acid added. For an organic acid, a salt with sodium or potassium can easily be formed. Because a molecule of salt is polar, it should be freely soluble in water, reaching a therapeutic solubility level. The other types of acids commonly used for salt formation with a weak base are sulfonic acids and carboxylic acids. 

This level of preformulation should be initiated in the beginning of the development cycle. The data consist of physicochemical properties of the chemical substance and analytical properties useful in the development of analytical methods, the evaluation of material quality, and testing for the acceptance of the formulation developed. In the early stage of development, the synthetic scheme is developed and the material available for preformulation may be limited. Thus the lack of supply quantities may affect the quality of data obtained. As the development cycle is pushed forward and the drug availability improves, data should be updated or refined with the use of more complicated and accurate methods. Part 1 of the preformulation report may be published before the establishment of specifications. The portion of this report consisting of analytical data may be known as an analytical profile in some organizations. 

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