Synthetic drug substances

Is the BCS that was developed with reference to chemically characterized and well-defined synthetic drug substances relevant for application and or adoption to botanical preparations (8) If one assumes, as is reasonable, that bioavailability of the active component(s) in a botanical dosage form depends on both solubility and permeability, the solubility of the botanical extract could be controlled through appropriate formulation technology and dissolution testing. The applicability of the BCS to botanical preparations will certainly be increasingly researched, debated, and discussed in the coming years. 

This chapter will mainly focus on the majority of drug formulations based on synthetic drug substances and their quality control or both. For biotechnological, food, medical, and environmental applications please refer to the relevant textbooks or other chapters of this book. 

For synthetic drug substances, purification is most often accomplished through crystallization. Preparative chromatography is currently more widely used for biotechnology-derived products than for synthetic drug substances... 

Description and Characterization. This section should provide a clear description of the physical and chemical properties of the synthetic drug substance, including the chemical structure, primary and subunit structure, molecu-... 

Downsized extremely sparingly soluble synthetic drug substances ... 

Metoprolol tartrate is a synthetic drug substance used for the treatment of hypertension (Fig. 1). The drug substance is a 2 1 salt that contains a racemic mixture of optical isomers of metaprolol and naturally occurring dextro-tartaric acid. Both the active ingredient and the tablet form have different testing requirements. 

Ramadan M, Goeters S, Watzer B, Krause E, Lohmann K, Bauer R, Hempel B, Imming P (2006) Chamazulene carboxylic acid and matricin a natural profen and its natural prodrug, identified through similarity to synthetic drug substances. J Nat Prod 69(7) 1041-1045... 

Endogenous substances such as serotonin, amino acids, purines, and pyrimidines all have biological activity and are tolerated in the human body. Therefore, these can be used in some cases as starting points for synthetic drugs. For example, the amino acid tryptophan and neurotransmitter... 

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. 

D-correlation spectra were collected. This information was used with empirical spectral simulations of proton and carbon spectra to elucidate the structures. The necessary information was thus provided to demonstrate that multiple dimer-like structures were formed through bonding of residual synthetic precursor to each of the hydroxyl sites of the drug substance itself. Three distinct dimers were identified. These species were tracked by LC-NMR, and two were shown to interconvert over time. Analogous trimer structures were also evident at lower levels. 

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. 

One of the first major pharmaceutical biotransformations was the development of the synthesis of hydrocortisone in the late 1940s by whole-cell hydroxylation (Figure 2.2). Up until then a 40-step synthetic route developed by the Noble Prize winning chemist R.B.Woodward was the only source of this important drug substance and intermediate. Nowadays, a biocatalyst exists for the selective hydroxylation of every position on the steroid nucleus. ... 

Eollowing finalization of drug substance synthetic routes and drug product formulation, the focus shifts to the development of robust and transferable methods for post-approval support at quality control units. It is important to remember during the final stage of method development that achievement of separation conditions is only one of the necessary parameters for successful method implementation. Extensive studies to measure robustness and quantitative method performance are conducted to assure that the method performs as intended in quality control laboratories. It should be emphasized that successful method development requires extensive cooperation between the development laboratory and the receiving quality control laboratories. 

During the course of chemical development, impurity profiles in drug substances may change due to changes in synthetic route and changes in the size of the batch. ICH guidelines for Impurities in New Drug Substances (ICH Q3A), require that impurity test results for... 

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