Excipients preformulation studies

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]. 

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,... 

Preformulation studies incorporate API qualification and evaluation of key excipients. Studies should incorporate studies of combinations of API and excipients and a rationale developed for the levels of various excipients chosen. Interactions between the API and excipients are expected and should not form the basis of altering the choice so long as data can be collected to show that the API is available through the shelf-life. 

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 order to develop a robust formula for a drug product (pharmaceutical dosage form) it is important to understand the chemical and physical properties of the API in conjunction with excipients that may be used to create the most stable product formula in terms of activity and potency. An outline of possible preformulation studies that should be conducted to ensure a proper and complete understanding of the chemical and physical properties of the API is presented in Table 3. 

Although they are often categorized as inert, preformulation studies can determine the inhuence of excipients on stability, bioavailability, and processability. Excipients are categorized into groups according to their main function, although some may be multifunctional, and examples of common excipients used in the manufacture of tablets and capsule are detailed in Table 3. 

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... 

With the results of the preformulation studies, the formulation scientist can begin to address some of the specific questions pertaining to the development of the final formulation. The state of the dosage form is selected. The inactive ingredients in the formulation, excipients, which promote stability of the final product, are screened. Finally, supportive accelerated stability studies are conducted to aid in the selection of the final formulation. 

Product quality can be compromised during manufacture, transport, storage or use. The causes of deterioration can be manifold and product-specific. They include microbial spoilage or chemical transformation of the active or physical changes that alter performance in vivo. Deterioration can compromise safety or make the medication less attractive, which means it may not be used. Excipients can contribute to or cause such changes unless carefully screened for possible interactions in preformulation studies. 

Preformulation testing of the specific API of interest and key excipients to be used in the product design stage, alone and in combinations with the API, should be included as a preliminary first step in the product and process development sequence. A simple check list of items worth consideration in preformulation studies with APIs and important or critical excipients is provided as follows ... 

The preformulation study tasks for the generic products are simpler than those for the original prescription products. By the time the generic product is marketed, the innovative drug product may have been sold for a long time. Most of the preformulation data and information have been published and can be found in publications such as the Analytical Profile for Drug Substances and Excipients and in the United States Pharmacopeia (USP) and foreign pharmacopoeia. 

In the preformulation study, the comprehension of physicochemical properties regarding water-solid surface interaction is beneficial to the handling, formulation, and manufacture of the finished products. Data on sorption/de-sorption isotherm, hydration of salts of drug product, water sorption of pharmaceutical excipients, and kinetics of water adsorption or desorption of a substance can be obtained effectively by the dynamic vapor sorption method. The knowledge may be utilized for dosage form design and supports the understanding of the mechanism of action. 

Important to quality control are the comparison and confirmation of drug substance identity, excipients, and packaging components. Techniques such as Fourier transform IR (FTIR), attenuated total reflectance (ATR), NIR, Raman spectroscopy are used with increased regularity. The detection of foreign metal contaminants is essential with inductively coupled plasma spectroscopy (ICP), atomic absorption (AA), and X-ray fluorescence. Also notable is the increased attention to analysis of chiral compounds, as in the synthesis of drug substances. Optical rotation, ORD, and CD are currently the preferred instruments for this practice. The analytical techniques commonly used in the preformulation study are discussed in the following. 

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). 

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