Drug/excipient interactions

Figure 4.50. Cumulative dissolution results. Two experimental tablet formulations were tested against each other in a dissolution test in which tablets are immersed in a stirred aqueous medium (number of tablets, constructional details and operation of apparatus, and amount of medium are givens). Eighty or more percent of the drug in either formulation is set free within 10 minutes. The slow terminal release displayed by formulation B could point towards an unwanted drug/excipient interaction. The vertical bars indicate ymean - with Sy 3%. A simple linear/exponential model was used to approximate the data for the strength 2 formulation. Strengths I and 3 are not depicted but look very similar.

JTH Ong, ZT Chowhan, GJ Samuels. Drug-excipient interactions resulting from powder mixing VI. Role of various surfactants. Int J Pharm 96 231-242, 1993. 

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 very early that diffuse reflectance spectroscopy could be used to study the interactions of various compounds in a formulation, and the technique has been particularly useful in the characterization of solid state reactions [24]. Lach concluded that diffuse reflectance spectroscopy could also be used to verify the potency of a drug in its formulation. In addition, studies conducted under stress conditions would be useful in the study of drug-excipient interactions, drug degradation pathways, and alterations in bioavailability owing to chemisorption of the drug onto other components in the formulation [24]. 

The topics of polymorphism and pseudopolymorphism dominate the majority of publications that deal with utilizing infrared spectroscopy for the physical characterization of pharmaceutical solids. Typically, in each of the publications, IR spectroscopy is only one technique used to characterize the various physical forms. It is important to realize that a multidisciplinary approach must be taken for the complete physical characterization of a pharmaceutical solid. Besides polymorphism, mid- and near-IR have been utilized for identity testing at the bulk and formulated product level, contaminant analysis, and drug-excipient interactions. A number of these applications will be highlighted within the next few sections. 

Bulk drug 13C, 31P, 1SN, 25Mg, 23Na Solid state structure elucidation, drug-excipient interaction studies (variable temperature), (pseudo)polymorphic characterization at the qualitative and quantitative level, investigation of hydrogen bonding with salt compounds... 

Tablets 13C, 31P Drug-excipient interaction studies, (pseudo)-polymorphic characterization at the qualitative and quantitative levels...

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. 

Thermal methods have found extensive use in the past as part of a program of preformulation studies, since carefully planned work can be used to indicate the existence of possible drug-excipient interactions in a prototype formulation [2], It should be noted, however, that the use of differential scanning calorimetry (DSC) for such work is less in vogue than it used to be. Nevertheless, in appropriately designed applications, thermal methods of analysis can be used to evaluate compound purity,... 

Crawley, P., Drug-excipient interactions, Pharm. Tech Eur., 13, 2001, 26. 

Chowhan, Z. T.. and Chi, L. H. Drug-excipient interactions resulting from powder mixing. Part 3. Solid-state properties and their effect on drug dissolution. J. Pharm. Sci. 75 534-541, 1986. 

Factors affecting the delivery include the physical form of the drug, the entry into the body, the design and the formula of the product. This may depend on the physicochemical properties of the excipients, the control of the drug-excipient interaction at the absorption site. Thus, polysaccharides may play an essential role for effectiveness and reliability of the different drug delivery systems. 

McDaid FM, Barker S A, Fitzpatrick S, Petts CR, Craig DQM. Further investigations into the use of high sensitivity differential scanning calorimetry as a means of predicting drug-excipient interactions. Int J Pharm 2003 252 235-240. 

Schildcrout SA, Risley DS, Kleeman RL. Drug-excipient interactions of seproxetine maleate hemi-hydrate isothermal stress methods. Drug Dev Indust Pharm 1993 19(10) 1113-1130. 

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