Compatibility drug/excipient interactions

The sample temperature is increased in a linear fashion, while the property in question is evaluated on a continuous basis. These methods are used to characterize compound purity, polymorphism, solvation, degradation, and excipient compatibility [41], Thermal analysis methods are normally used to monitor endothermic processes (melting, boiling, sublimation, vaporization, desolvation, solid-solid phase transitions, and chemical degradation) as well as exothermic processes (crystallization and oxidative decomposition). Thermal methods can be extremely useful in preformulation studies, since the carefully planned studies can be used to indicate the existence of possible drug-excipient interactions in a prototype formulation [7]. 

It was recognized quite some time ago that DTA analysis could be used to deduce the compatibility between a drug substance and its excipients in a formulation. The effect of lubricants on performance was as problematic then as it is now, and DTA proved to be a powerful method in the evaluation of possible incompatibilities. Jacobson and Reier used DTA to study the interaction between various penicillins and stearic acid [17]. For instance, the addition of 5% stearic acid to sodium oxacillin monohydrate completely obliterated the thermal events associated with the antibiotic. Since that time, many workers employed DTA analysis in the study of drug-excipient interactions, although the DTA method has been largely replaced by differential scanning calorimetry technology. 

Incompatibilities have also been observed in solid dosage forms. A typical tablet contain binders, disin-tegrants, lubricants and fillers. Compatibility screening for a new drug should consider two or more excipients from each class. Serajuddin et al. have developed a drug-excipient compatibility screening model to predict interactions of drug substances with excipients [49],... 

Other examples of the use of microcalorimetry to study drug-excipient compatibility in the solid state are provided by Selzer et al. (30), who studied the interaction between a solid drug and a range of excipients [including potato starch, a-lactose-monohydrate, microcrystalline cellulose (MCC), and talc] and Schmitt (31) who used water slurries instead of humidified samples. 

In conclusion, drug-excipient compatibility studies have a key role at the early preformulation stages to select excipients or after formulation to help identify the mechanism of any detected instability [14], An understanding of the potential physicochemical interactions of drug with known chemical reactivities of excipients and... 

Cyclodextrins (CDs) have a wide range of application in the pharmaceutical field due to their unique structure, which allows them to include hydrophobic molecules in their apolar cavity and to mask the physicochemical properties of the included molecule. This results in the enhancement of drug bioavailability by improving aqueous solubility and the physical and chemical stability of the drug, masking undesired side effects such as irritation, taste, or odor, and overcoming compatibility problems or interactions between drugs and excipients. 

The drug-excipient compatibility screening model developed by Serajuddin et al. [25] could be used to determine potential stability problems due to interactions of API with excipients in solid dosage forms. Table 15-4 shows an example of binary and ternary mixtures employed by Serajuddin et al. 

Compatibility testing using isothermal microcalorimetry is used mainly as a screen for drug/excipient chemical interactions and not as a quantitative means of analysis. This is because, at present, it is not possible to obtain information about the quantity of material at the active surface in the solid state (see chemical stability in the solid state section 3.2). 

The dibasic calcium phosphate dihydrate example discussed above is probably an extreme example of the instability of an excipient relating to the release of water. But many excipients exist in a hydrated state, and heating them for the purposes of compatibility studies, or accelerated stability testing, can cause any free water, and sometimes other types of water, to be released, which can then influence any potential interaction, or even interact itself with the drug. 

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