Preformulation studies excipient compatibility

The compatibility of the active ingredient with other active ingredients and excipients should be demonstrated. Preformulation study reports often provide useful relevant information. Preliminary stability study reports may be used as supporting data. 

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]. 

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. 

In conclusion, drug-excipient compatibility studies have a key role at the early preformulation stages to select excipients or after formulation to help identify the mechanism of any detected instability [14], An understanding of the potential physicochemical interactions of drug with known chemical reactivities of excipients and... 

Moreover, if adequate forced degradation studies (i.e., acid/base hydrolysis) are performed in the early preformulation stage, the identification of a potential degradation product that might arise during excipient compatibility... 

Although there has been some debate in the literature about the nature of compatibility testing and the value of results (e.g., see Monkhouse and Maderich 1989, and Monkhouse 1993), it is felt that it still has some relevance to pharmaceutical preformulation. Essentially, there are four major stages in drug-excipient compatibility studies, but before considering such studies, it is worth checking whether there are any known incompatibilities, as is shown in Table 6.17 (Monkhouse 1993). 

At the early stages of optimisation, preformulation studies are usually conducted to screen excipients or packaging materials and to select those compatible with the candidate drug, using accelerated stress testing procedures. More details about the preformulation techniques, which can be employed for compatibility studies, are discussed in Chapter 3. The importance of doing compatibility studies is for reducing the number of excipients and formulation options to test in further product optimisation studies. 

The problem of preformulation studies for screening of excipients to know their compatibility with the drug substance, given in table 2.8, is here simplified by reducing the number of possibilities in each class of excipient (factor) to 2 (9). For this illustration we will also eliminate the final variable, the presence or not of a gelatine capsule shell. The excipients tested and their concentrations are therefore those of table 2.10. 

Before process validation can be started, manufacturing equipment and control instruments, as well as the formulation, must be qualified. The formulation of a pharmaceutical product should be studied in detail and qualified at the development stage, i.e., before the application for the marketing authorization is submitted. This involves preformulation studies, studies on the compatibility of active ingredients and excipients, and of final drug product and packaging material, stability studies, etc. 

Because key excipients are well established in most new product and process development programs, the same degree of preformulation scrutiny is often not required. Compatibility studies with the API, however, should be performed to study possible untoward interactions between the active ingredients and the excipients. It should be kept in mind that small or minor changes in physical and possibly chemical properties upon intimate contact in binary studies with key excipients should not automatically exclude a favored excipient without further critical testing. 

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