Excipient mechanisms

The authors determined the mechanical properties of the excipients in this manuscript at or near 0.85 SF except for dicalcium phosphate (DCP). The low SF that could be achieved with DCP ( 0.6) demonstrates that its compressibility was less than the compressibility of the other materials and that relevant comparisons to them could not be easily made. When the SF difference between materials is 0.03 or less, property differences due to SF are normally relatively small and comparisons can be made with confidence, but when the SF difference is greater than 0.03, a meaningful material comparison becomes more difficult to achieve. In that situation, material comparisons using only general qualitative statements are appropriate. The latter scenario was the case with DCP, and this has been discussed in the section Calcium Phosphate Dibasic. In the discussions that follow, excipient mechanical properties were determined at a SF of 0.85 unless otherwise noted. 

Finally, knowledge of excipient mechanical and physical properties is essential to creating a robust formulation that manufactures tablets that meet specifications in a time- and material-efficient manner. Excipient selection must also take into consideration API stability and biopharmaceutical performance of the dosage form. Uneducated selection of excipients will likely lead to numerous formulating iterations that require much time and material, which are luxuries that product development scientists do not have in the competitive pharmaceutical environment. 

Ghyczy, M. and Boros, M. Phosphatidylcholine as active drug substance and as excipient, mechanism of biological acitivity. in Nutrition and Biochemistry of Phospholipids, Szuhaj, B. and Nieuwenhuysen, v.W. eds., Champaign, Illinois AOCS, 2002 pp. 234-41. 

Convincing evidence for a surface erosion process is shown in Fig. 8, which shows the concomitant release of the incorporated marker, methylene blue, release of the anhydride excipient hydrolysis product, succinic acid, and total weight loss of the device. According to these data, the release of an incorporated drug from an anhydride-catalyzed erosion of poly (ortho esters) can be unambiguously described by a polymer surface erosion mechanism. 

A plausible mechanism for the erosion of devices that contain Mg(OH)2 is shown in Fig. 14 (2). According to this mechanism, the base stabilizes the interior of the device and erosion can only occur in the surface layers where the base has been eluted or neutralized. This is believed to occur by water intrusion into the matrix and diffusion of the slightly water-soluble basic excipient out of the device where it is neutralized by the external buffer. Polymer erosion then occurs in the base-depleted layer. 

At the time these studies were conducted, the role of acidic excipients was not clearly understood, but the observed bulk erosion is of course consistent with the mechanism shown in Fig. 6. Consequently, if gross bulk erosion is to be avoided and long-term erosion control of levonorgestrel achieved, it is necessary to stabilize the device interior. To do so, devices with incorporated Mg(OH)2... 

For most tablets, it is necessary to overcome the cohesive strength introduced into the mass by compression. It is therefore common practice to incorporate an excipient, called a disintegrant, which induces this process. Several types, acting by different mechanisms, may be distinguished (a) those that enhance the action of capillary forces in producing a rapid uptake of aqueous liquids, (b) those that swell on contact with water, (c) those that release gases to disrupt the tablet... 

It may sometimes by necessary to supplement the properties of the drug so that it compresses more easily, and these needs have been realized by several manufacturers of excipients. Materials described as compression aids are now commercially available. Ideally, such adjuvants should develop mechanical strength while improving, or at least not adversely affecting, release characteristics. Among the most successful at meeting both these needs have been the microcrystalline celluloses (partially acid-hydrolyzed forms of cellulose). A number of grades are available based upon particle size and distribution. 

As a generalization, increasing compressional force will retard dispersion on administration, and therefore, levels should be kept as low as possible, consistent with achieving acceptable mechanical properties. With some excipients there is a critical compressional force range required to achieve minimum disintegration times. 

To produce tablets that are uniform in weight and content and exhibit a certain degree of mechanical strength, one needs a mixture of powders with (a) good flow properties (b) a minimum tendency for segregation, and (c) the ability to be compressed. To achieve these ends, granulation with other excipients is often necessary. 

Solvents used to increase solubility for compounds during screening of permeability across the cell monolayers, together with commonly used excipients for formulations, can also affect the barrier as they contain ingredients which enhance drug absorption [100, 151]. There are different mechanisms by which these compounds can modulate the barrier [4, 149, 150] for example, they may increase the tight junctional pathway inhibiting carrier-mediated transport, or cholesterol... 

Table 9 Lot to Lot Variations of the Mechanical Properties of Some Common Drugs and Excipients Determined at a Compact Solid Fraction of 0.8 to 0.9...

Yapp, F. S., Adams, M. J., Seville, J. P. K., Zhang, Z. Single and bulk compression of pharmaceutical excipients Evaluation of mechanical properties. Powder Technol., 185, 2008, 1-10. 

H-bonding potential Molecular weight/size PSA Intestinal metabolism Transport mechanisms Native surfactants Intestinal secretions, e.g. mucous, enzymes Intestinal blood/lymph flow Excipient effects... 

While there are limitations associated with the use of an in vitro permeability model for assessing the transport of compounds across the buccal mucosa, it can still be useful in assessing and comparing the permeability of compounds under different conditions, such as pH, temperature, and osmolarity, which provide valuable information on the mechanisms involved in drug transport. Additionally, the preliminary effects of potential chemical penetration enhancers or formulation excipients may be assessed, and these may provide a substantial rationale for subsequently assessing the effect of these agents in man. 

We now turn briefly to the problem of peptide stability in the solid state [8] [88], First, we note that most - if not all - reactions discussed in the previous and subsequent sections can also occur in the solid state, although the kinetics and mechanisms of the reactions can be quite different from those observed in solution. Moisture content, the presence of excipients that act as catalysts, and surface phenomena are all factors whose roles are all-but-im-possible to predict. As a result, each formulation poses a new challenge to pharmaceutical scientists. As a rule, solution data cannot be used to predict the shelf-life of solid formulations, and extrapolating from one solid formulation to another can be misleading. 

The study of reaction rates or kinetics of a particular denaturation process of a protein therapeutic can provide valuable information about the mechanism, i.e., the sequence of steps that occur in the transformation of the protein to chemically or conformationally denatured products. The kinetics tell something about the manner in which the rate is influenced by such factors as concentration, temperature, excipients, and the nature of the solvent as it pertains to properties of protein stability. The principal application of this information in the biopharmaceutical setting is to predict how long a given biologic will remain adequately stable. 

It should be noted that the unfolding kinetics can sometimes involve quite complex unfolding schemes of different substates in equilibrium with the native state. Staphylococcal nuclease is an example of such behavior, known to unfold with three different substates that exhibit an equilibrium that does not appear to shift with temperature.49 Irreversible aggregation processes of proteins have been known to involve first- or second-order reactions.132141 The mechanism of recombinant human interferon-y aggregation is an example where thermodynamic and kinetic aspects of the reaction provided a powerful tool for understanding the pathway of instability and permitted a rationale for screening excipients that inhibited the process.141... 

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