Excipient interaction with

In these various contexts, excipients and issues associated with them can be considered in the following different areas. Functionality An excipient interacts with the active in the formulated dosage form and/or provides a matrix that... 

Mendes, R.W. Anaebonam, A.O. Daruwala, J.B. Chewable tablets. In Pharmaceutical Dosage Forms Tablets, Lieberman, H.A., Lachman, L., Schwartz, J.B., Eds. Marcel Dekker, Inc. New York, 1989 I, 362-387. Richards, R.M. Xing, J.Z. Mackay, K.M. Excipient interaction with cetylpyridinium chloride activity in tablet based lozenges. Pharm. Res. 1996, 13 (8), 1258-1264. 

Richards RM, Xing JZ, Mackay KM. Excipient interaction with cetylpyridinium chloride activity in tablet based lozenges. Pharm Res 2003 13(8) 1258-1264. 

The analysis of a pharmaceutical tablet (6) requires sample preparation that is little more complex as most tablets contain excipients (a solid diluent) that may be starch, chalk, silica gel, cellulose or some other physiologically inert material. This sample preparation procedure depends on the insolubility of the excipient in methanol. As the components of interest are both acidic and neutral, the separation was achieved by exploiting both the ionic interactions between the organic acids and the adsorbed ion exchanger and the dispersive interactions with the remaining exposed reverse phase. 

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.

Diffuse reflectance spectroscopy was used to screen the possible interactions between a large number of adjuvants and several dyes [23]. It was concluded that supposedly inert excipients (such as starch or lactose) were capable of undergoing significant reactions with the dyes investigated (Red No. 3, Blue No. 1, and Yellow No. 5). For adjuvants containing metal ions (zinc oxide, or calcium, magnesium, and aluminum hydroxides), the degree of interaction could be considerable. It was concluded from these studies that dye-excipient interactions could also be responsible for the lack of color stability in certain tablet formulations. 

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... 

An increased rate of dissolution resulting from particle size reduction has also been observed for several excipients. For example, griseofulvin systems containing ethylcellulose of size fraction 710-850 /im released the drug almost 25% faster than the same systems containing ethylcellulose of size fraction 1000-2000 fim. The authors interpret these results in terms of more excipient particles being available to interact with the drug in the fraction of lower size [69],... 

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. 

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. 

Tablet excipient interactions are occasionally observed when evaluating a drug product for purity. Since there are many excipients in a typical pharmaceutical tablet, known bands need to be identified to make it easier to evaluate for degradation products. Unfortunately, occasionally an inert excipient may react with a derivatizing agent used in TLC making this entity appear as a band that now needs to be identified. In Fig. 13.33, a placebo tablet, an extracted tablet, a handmade tablet blend of all components, and the drug substance standard are all applied to the same HPTLC plate and developed. These results alert the analyst to any excipients that may interfere in the evaluation of the tablet for purity. In this case, the only bands observed in the tablet blend and extracted tablet are the same bands seen in the tablet blend.

The Committee for Proprietary Medicinal Products [8] applied the BCS, with certain requirements, to dispense with bioequivalency tests if the active pharmaceutical ingredient is class I and the in vitro dissolution of the finished dosage form is fast [9], An active substance is considered highly soluble if the amount contained in the HDS of an IR product is dissolved in 250 ml of each of three buffers within the range of pH 1-8 at 37°C (e.g., pH 1.0, 4.6, and 6.8). There should be linear and complete absorption, which indicates HP to reduce the possibility of an IR dosage form influencing the bioavailability [8], The similarity of the dissolution profiles of the test and reference products is demonstrated in each of three buffers within the range of pH 1-8 at 37°C (e.g., pH 1.0,4.6, and 6.8). If there is rapid dissolution of the product, where at least 85% of the active substance is dissolved within 15 min, no further comparison of the test and reference is required. Further requirements include that excipients be well established and have no interaction with the pharmacokinetics of the active substance and that the method of manufacture of finished product... 

Several dosage forms carry an increased risk of degradation or adjunct formation. Products such as injections and aerosols are more likely to interact with volatiles or extractables from packaging and closure systems. Tablets have the potential to form adjuncts with excipients (specifically, lactose has been shown to form adjuncts in tablets). Non-CFC propellants in aerosols have a large number of impurities that typically do not interact with drug substances, but the potential for these interactions does still exist. Creams, ointments, lotions, and other such products will each have specific interactions that should be considered while evaluating the impurity profile of a drug product. 

Drug products contain both drug substance (sometimes referred to as the Active Pharmaceutical Ingredient [API]) and excipients. The resultant biological, chemical and physical properties of the dmg product are directly dependent on the excipients chosen, their concentration and interactions with the API [1]. 

This assay is altogether more difficult since three active ingredients are involved and several excipients interfere in the analysis, including one major excipient (methylparaben), which is not removed in the extraction process. In addition the active ingredients are bases which have a tendency to interact with any uncapped silanol groups in the stationary phase and it is essential to use a column which is deactivated with respect to the analysis of basic compounds. The three active ingredients are all at different concentrations in the formulation so that attention has to be paid to selection of a detection wavelength at which each component can be detected. In this particular assay a DAD would be useful. 

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