Synthetic drug substances testing

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. 

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. 

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... 

Supporting Data — Data, other than those from formal stability studies, that support the analytical procedures, the proposed retest period or shelf life, and the label storage statements. Such data include (1) stability data on early synthetic route batches of drug substance, small-scale batches of materials, investigational formulations not proposed for marketing, related formulations, and product presented in containers and closures other than those proposed for marketing (2) information regarding test results on containers and (3) other scientific rationales. 

Some chiral drug substances either occur naturally or are synthetic derivatives of natural products. In these cases, the controls on the raw materials are often assumed to guarantee the stereochemical identity of the finished bulk drug substance product without the use of a specific stereochemically sensitive test. Such an assertion is of little significance for regulatory purposes. First, determination of the source species for an... 

It is absolutely essential that the accuracy be validated with the same quantitation method that is used in the control test procedure. Recovery deviations from the theoretical values while performing a calibration with a drug substance alone may indicate interferences between the analyte and placebo components. In such a case, the calibration should be done with a synthetic mixture of placebo and drug substance standard. Such interferences may also be detected by the separate determination of linearity for dilutions of the drug substance and for a spiked placebo. 

Numerous methods are required to characterize drug substances and drug products (Chapter 10). Specifications may include description identification assay (of composite sample) tests for organic synthetic process impurities, inorganic impurities, degradation products, residual solvents, and container extractables tests of various physicochemical properties, chiral purity, water content, content uniformity, and antioxidant and antimicrobial preservative content microbial tests dissolution/disintegration tests hardness/friability tests and tests for particle size and polymorphic form. Some of these tests may be precluded, or additional tests may be added as dictated by the chemistry of the pharmaceutical or the dosage form. 

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. 

Table 9.9 shows a summary of validation results for the composite test method for a drug substance shown in Figure 9.9. The development process of this particular method is described in Chapter 8, Section 8.8.2. The key analytes of this assay are the API, an impurity eluting (impurity 1) at 6.4min that has been identified as an isomer of the API and the immediate synthetic precursor eluting at 7.6min. 

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