Formulations 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.

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. 

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,... 

In the pharmaceutical industry, SSNMR is commonly used to study polymorphism, hydrogen bonding, crystal packing, and solid-solid interactions. Shelf life or activity decay is often determined by the bioavailability of different polymorphs. Fig. 12 shows very different CP/MAS spectra from two polymorphs of an analgesic, flufenamic acid. It is also used for the study of inclusion complexes, drug-excipient interactions, or the effect of moisture on drug substances or formulations. 

Other applications of DSC and other TA techniques to the pharmaceutical industry include physico-chemical interactions (275), polymorphism in triglyceride suppository formulations (276) drug-excipient interactions (277), and many more. Reviews of the applications of DTA/DSC and different techniques to pharmaceuticals include those by Brennan (278), Daly (279), and others (280). 

The main objectives in tablet characterization are to identify drug-excipients interactions, quantitation of the amount of active substance per tablet, to identify the solid form present and to observe changes with storage conditions (stability). All of these findings, taking into account that in tablet formulations the API concentration can be very low and the signals of excipients usually dominate the spectrum, make SSNMR characterization a challenge. 

A comparison of the carbon SSNMR spectra of the manufactured formulation to that of the equivalent physical mixture, both shown on the left of Fig. 10.25, shows no significant differences. The chemical shift and line shape differences between the top and bottom carbon spectra in the figure are minor and thus do not themselves prove an interaction between the API and excipients. Small spectral differences such as these may arise from minor fluctuations in sample temperature, for instance. One may, albeit incorrectly, conclude at this point that no drug-excipi-ent interactions exist. However, as we shall soon see, it is risky to make such conclusions based on the lack of an observed change. 

To continue the investigation, carbon detected proton T relaxation data were also collected and were used to calculate proton T relaxation times. Similarly, 19F T measurements were also made. The calculated relaxation values are shown above each peak of interest in Fig. 10.25. A substantial difference is evident in the proton T relaxation times across the API peaks in both carbon spectra. Due to spin diffusion, the protons can exchange their signals with each other even when separated by as much as tens of nanometers. Since a potential API-excipient interaction would act on the molecular scale, spin diffusion occurs between the API and excipient molecules, and the protons therefore show a single, uniform relaxation time regardless of whether they are on the API or the excipients. On the other hand, in the case of a physical mixture, the molecules of API and excipients are well separated spatially, and so no bulk spin diffusion can occur. Two unique proton relaxation rates are then expected, one for the API and another for the excipients. This is evident in the carbon spectrum of the physical mixture shown on the bottom of Fig. 10.25. Comparing this reference to the relaxation data for the formulation, it is readily apparent that the formulation exhibits essentially one proton T1 relaxation time across the carbon spectrum. This therefore demonstrates that there is indeed an interaction between the drug substance and the excipients in the formulation. 

---