Excipient compatibility with APIs

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. 

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. 

In summary, the (advanced) treatment processes are not compatible with sustainable development as they are end-of-the-pipe technologies and not affordable in all countries. The presence of synthetic chemicals such as APIs and pharmaceutical excipients in water demonstrates that conventional effluent treatment is not effective. 

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. 

Minimally, one should have a brief foreknowledge of the thermal and thermal/humidity solid-state stability of the API prior to initiation of excipient compatibility studies. These protocols should include investigation of stability at various temperature and humidity conditions and should always include information about both chemical stability and physical-form integrity of the API. Thermal and thermal moisture-induced solid-state chemical reactions are well known (5), with hydrolysis and oxidation being the most prevalent mechanisms of decay. Changes in physical form with thermal and... 

Overall, the concepts presented in this summary suggest that (i) an initial understanding of the properties of the API and excipients should be utilized to design excipient compatibility studies, (ii) the understanding of the role of water in the interactions of excipients with API should be considered for all designs of compatibility testing, and (iii) the physical form and its involvement in the solid state needs to be considered when interpreting the data. 

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. 

Spin coating is a smaU-scale rapid method for ASD screening that requires minimum amounts of API. Sample preparation is simple and the technique is compatible with a number of analytical characterization methods. Automation of the process is possible but parallel processing obviously has certain Umitations. Similar to solvent casting approaches, the level of residual solvent after evaporation can be an issue, and the compounds need to dissolve and remain stable in the same volatile solvents (e.g., ethanol, acetone, etc.) as the polymers and/or other excipients used. 

Stability studies are required to run for a longer duration in support of phase II clinical studies. During this phase, the technical focus shifts to development of a commercially viable formulation. In this regard, excipient compatibility studies, multiple formulations, and packaging materials are generally screened. In most cases, short-term (6-month maximum) probe stability data are sufficient, followed by longer term (2-3 years) studies for the selection of the best formulation candidate. The API should also be monitored for stability with studies lasting up to 5 years in duration. 

In addition, simple binary studies with key excipients should be done to establish physical and chemical compatibility between the API and the selected excipient. These studies need not be elaborate, but will provide useful information to the formulator during the critical drug product development stage. 

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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