Excipients compatibility

Incompatibilities have also been observed in solid dosage forms. A typical tablet contain binders, disin-tegrants, lubricants and fillers. Compatibility screening for a new drug should consider two or more excipients from each class. Serajuddin et al. have developed a drug-excipient compatibility screening model to predict interactions of drug substances with excipients [49],... 

Application of DSC and HPLC to determine the effects of mixture composition and preparation during the evaluation of niclosamide-excipients compatibility showed that although some reactions occurred, niclosamide was compatible with a majority of common tablet excipients tested [63],... 

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]. 

Serajuddin, A.T.M., Thakur, A.B., Ghoshal, R.N., Fakes, M.G., and Varia, S.A., Selection of solid dosage form composition through drug-excipient compatibility testing, /. Pharm. Sci., 88, 696, 1999. 

Schmitt, E.A., Peck, K., Sun, Y., and Geoffroy, J-M., Rapid, practical and predictive excipient compatibility screening using isothermal microcalorimetry, Thermochim. Acta, 380, 175, 2001. 

The candidate method is used to support drug synthesis, excipient compatibility, and ultimately to evaluate candidate formulations. Such support typically involves analyses of stressed materials to identify degradation trends. These studies are conducted in the solid state by exposing the DS and DP to relative humidity, temperature, light, and oxidizing... 

In the typical dmg-excipient compatibility testing program, binary powder mixes are prepared by triturating API with the individual excipients. These powder samples, usually with or without added water and occasionally compacted or prepared as slurries, are stored under accelerated conditions and analysed by stability-indicating methodology, for example, HPLC, CE and so forth. This entire process takes considerable time and resources. 

However, as might be anticipated, there is no universal panacea to drug stabilisation. Basic excipients can also destabilise formulations. Serajuddin et al. [19] reported on the drug-excipient compatibility of a calcium channel... 

Crowley and Martini [48] reported on several studies evaluating the impact of unit process operations on hydrates. AU showed some level of dehydration liberating freed crystalline water to participate in moisture-mediated reactions. The authors speculated that such energetic processing conditions are likely to have a similar affect on hydrated excipients with a potential deleterious effect on moismre-sensitive APIs. They commented that classical excipient compatibility studies were ill-equipped to predict such moismre-mediated interactions and that compression, attrition and other energy-intensive unit operations were rarely mentioned as requiring investigations. 

Desai et al. [86] reported on the photolytic degradation of the anti-viral, sorivudine, which formed the inactive Z-isomer. On the basis of extensive dmg-excipient compatibility studies it was found that the incorporation of iron oxide pigments into the blends (direct compression or wet granulated) stabilised the dmg to photodegradation indeed, so much so that the tablet was found not to require a film coat. The data are summarised in Table 2.6. 

J. I. Wells, Pharmaceutical Preformulation, Excipient Compatibility, Ellis Horwood, Chichester, Chapter 8, 1988. 

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... 

Excipient compatibility studies are an important part of any preformulation screen for a new API. However, it is important to remember that an excipient compatibility screen can only indicate the excipients to be avoided because of an obvious chemical incompatibility. The results from excipient compatibility studies are not always easy to interpret, particularly if a physical interaction is found. As stated above, physical interactions can be detected using some form of calorimetry in conjunction with, e.g., chromatography, but the interpretation of the significance of the interaction probably requires prior experience of the excipient and its interactions. It is difficult to predict that the molecular structure of the excipient will interact physically with the chemical structure of the API molecule. 

Excipient compatibility studies are a form of preliminary stability assessment. It is important that they be executed appropriately. The precise details of the testing will probably be different for each organization carrying out such studies. However, certain general assumptions are implicit in this approach. The underlying principle is the Arrhenius relationship ... 

There are two main approaches to excipient compatibility screening isothermal studies at an elevated temperature and variable temperature studies in which the temperature is steadily increased, as in DSC. Both approaches are valid, but it is important to note, as has been stated above, that excipient compatibility testing is not a definitive test. We cannot state that an interaction will not take place, even though one may not have been found. We can only state which excipients to avoid because there is a very obvious interaction. A typical scheme is given in Figure 1 for a DSC-based excipient compatibility study. (There are other schemes that are used successfully.)... 

Excipient compatibility and stability studies rely on two underlying assumptions. One is that there is no change in reaction mechanism as temperature increases the second is that the excipient is also chemically stable under the conditions of test. However, if the reaction mechanism does change with temperature, it is likely the result will show a disproportionately greater breakdown than would be anticipated from lower temperature studies. Thus the risk is that an excipient is rejected that might in reality be perfectly suitable for the formulation. In many cases this is probably an acceptable risk. 

The stability of excipients is almost always taken for granted. Obviously, there is the potential for a phase change with certain lower melting excipients, e.g., semisolid materials, however, this is not a chemical phenomenon although it may enhance the potential for interaction by increasing the effective interface available at which the interaction can take place. However, some materials are not stable under conditions encountered in excipient compatibility screening or accelerated stability testing. A notable example is dibasic calcium phosphate dihydrate. At temperatures as low as 37°C, under certain conditions, the dihydrate can dehydrate to form the anhydrous material with the concomitant loss of water of crystallization (25), and at 25°C, it is a stable solid with a shelf life, when stored correctly, of more than two years. 

The objective of the excipient compatibility screening is to quickly find those excipients/processes that should be avoided for the particular API. In order to obtain a result as rapidly as possible we carry out these studies at elevated temperature as discussed above. The question arises as to how long and at what temperature We need to be able to extrapolate the results to a convenient time frame at 25°C/ 60% RH for ICH Climatic Zones I and II (or 30°C/65% RH for ICH Climatic Zones III and IV). Based on the approximation from the Arrhenius equation (see above) that the reaction rate doubles for a 10°C rise in temperature, we have standard multipliers that have been widely accepted within the pharmaceutical industry. For example, a study carried out at 40° C for one month would equate to three... 

Figure 1 DSC-based excipient compatibility testing program.

Chrzanowski FA, Ulissi LA, Fegely BJ, Newman AC. Preformulation excipient compatibility testing application of a differential scanning calorimetric method versus a wet granulation simulating, isothermal stress method. Drug Devel Ind Pharm 1986 12(6) 783-800. 

Serajuddin, A. T. M., A. B. Thakur, R. N. Ghoshal, M. G. Fakes, S. A. Ranadive, K. R. Morris, and S. A. Varia. 1999. Selection of dosage form composition through drug-excipient compatibility testing. 

Formulation profile, which consists of physical and chemical characteristics required for the products, drug-excipient compatibility studies, and the effect of formulation on in vitro dissolution... 

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