Excipient Interactions

On their own, most bulk APIs are not particularly convenient for the patient. Ignoring taste concerns, etc., we might be able to give the patient a bag of acetaminophen powder with the instruction to take one level teaspoonful four times a day. But how would the patient cope with digoxin presented in a similar manner Does the average patient understand the concept of a microgram We formulate drugs to make them suitable and convenient for use by the patient. 

In order to develop and manufacture a medicine, we need to consider three main components  

For some types of product we may also need to consider the primary packaging. Very often, it can be as important to understand the limitations of these three components as it is to understand their properties or advantages. Beyond these three 

Excipients are thus one of the three components that in combination produce the medicine that the patient will take. In therapeutic terms, the API is of primary importance because without it there is no treatment and no product. However, in terms of the development and manufacture of the product, all three components are equally important, and we neglect any one of them at our peril. The annals of formulation development in most companies, both large and small, are probably littered with examples where some aspect of one of these three components has been neglected in some way, with unfortunate consequences for the project. The interactions between excipients and the other two components (the API and the manufacturing process), and/or between two or more excipients, are fundamental to the transformation of an API into a medicinal product. 

In a sense, formulation science and pharmaceutics may be described as the investigation and application of interactions between excipients, the API, and the manufacturing process. The formulation scientist brings expertise in the use of excipients and pharmaceutical processing, and then adds an understanding of the API. In this discussion we will be considering only the interactions of excipients, but we must remember that the other two components, the API and the manufacturing process, can also interact with each other. 

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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. 

S. T. Tzannis and S. J. Prestrelski, Moisture effects on protein-excipient interactions in spray dried powders. Nature of destabilizing effects of sucrose, J. Pharm. Sci, 88(3), 360 (1999). 

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]. 

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. 

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,... 

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. 

Fortuitously for this project, the drug substance, and not the excipients, contained a fluorine moiety. Fluorine-19 MAS spectra were therefore also acquired at 500 MHz on the two samples, and they are shown to the right of the corresponding carbon spectra for each sample in Fig. 10.25. The fluorine-19 chemical shifts are sensitive enough in this example to show the API-excipients interaction directly. This is evident from the dramatic change in spectral line shape. 

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.

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

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... 

Excipient interactions are a large part of why medicines work (and sometimes why they do not work in development). They can be either beneficial or detrimental, and can be classified simply as... 

Many in the pharmaceutical industry, when they hear the term excipient interactions, think immediately of excipient compatibility studies. These studies are important in the development of new products, but as we shall discuss, they are only a small part of the overall scope of excipient interactions. The significance of excipient interactions can extend well beyond the development of the particular medicinal product. Excipient interactions can have implications for... 

Many interactions will directly influence the efficacy of the product, and thus potentially the health and/or treatment of the patient. However, it must be reemphasized that excipient interactions are not always detrimental. Sometimes they can be used to our advantage, particularly in the areas of product manufacture and drug delivery systems (see below). 

Some excipients are specifically formulated as mixtures to obtain the required performance. Such excipients are often referred to as being coprocessed or compounded. These excipients make beneficial use of excipient-excipient interactions to derive improved functional performance in a particular type of application examples include... 

The presence of additives in the excipient is another issue that can directly influence our understanding of how a particular excipient interacts. The inclusion... 

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