Excipient compatibility example

In the following excipient compatibility example, drug substance was put on accelerated stability with different binary ratios of varied excipients and stored at 2 weeks and 4 weeks at dry and humid conditions, 50°C (dry) and 50°C/75% relative humidity, respectively (Figure 15-7). With most of the excipients under dry conditions, it was observed that the level of increase of degradation products in the binary mixtures was less than 0.2%. However, under 50°C/75%RH conditions, most of the excipients showed increasing degrada-... 

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. 

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... 

Other examples of the use of microcalorimetry to study drug-excipient compatibility in the solid state are provided by Selzer et al. (30), who studied the interaction between a solid drug and a range of excipients [including potato starch, a-lactose-monohydrate, microcrystalline cellulose (MCC), and talc] and Schmitt (31) who used water slurries instead of humidified samples. 

The nature of HSDSC instruments allows experiments to be run incorporating both isothermal and scanning steps. This enables rapid screens for excipient compatibility. An example is provided by the study of aspirin with two excipients using HSDSC (41). Figure 10 shows the HSDSC trace obtained for a binary mixture of acetylsalicylic acid (aspirin) with lactose and Figure 11... 

Information about excipients is useful in the initial planning and interpretation of the excipient compatibility results. Important factors to consider for excipients include their physical-chemical properties. The Handbook of Pharmaceutical Excipients lists important information on structure, moisture content, melting point, pH, solubility, and equilibrium moisture at variable relative humidity for individual excipients (27). An example of relevant physical-chemical parameters for some select excipients is detailed in Table 1. A spectroscopic review of excipients (28) has been completed, and extensive reviews of some of the most common types of excipients (i.e., carbohydrate based) are published (29). 

TABLE 10 Examples of Binary and Factorial Designs for Drug-Excipient Compatibility Studies ... 

TABLE 12-7. Example of Drug-Excipient Compatibility Testing Design. Reprinted with Permission from reference 59. 

The drug-excipient compatibility screening model developed by Serajuddin et al. [25] could be used to determine potential stability problems due to interactions of API with excipients in solid dosage forms. Table 15-4 shows an example of binary and ternary mixtures employed by Serajuddin et al. 

Starch is widely used in the pharmaceutical industry because, among its other properties, it is readily available, inexpensive, white, and inert. Excipient compatibility studies of starch and various active drugs have been performed using thermal methods of analysis. As an example, starch has been found to be compatible with cephalexin and acetylcysteine using this method of excipient screening. 

The use of DSC for studying such reactions allows the operator the possibility of obtaining not only empirical information regarding the temperature and time relationship for processes of interest but also more detailed kinetic parameters as outlined above. Clearly, the kinetic analysis may be considerably more complex when one considers non-Arrhenius behavior, and also takes into account issues such as the size and shape of the reacting species as may be the case for, for example, excipient compatibility reactions (21). Some more advanced kinetic functions are outlined in Chapter 5. 

The dibasic calcium phosphate dihydrate example discussed above is probably an extreme example of the instability of an excipient relating to the release of water. But many excipients exist in a hydrated state, and heating them for the purposes of compatibility studies, or accelerated stability testing, can cause any free water, and sometimes other types of water, to be released, which can then influence any potential interaction, or even interact itself with the drug. 

---