Formulation development Excipient compatibility screening

Figure 15-7. Excipient compatibility screening performed in early formulation development.

To reiterate a common theme, characterization of the crystalline form selected should be extensive in order to assure a sound scientific understanding of the material properties of the substance is in hand during the development process. An appreciation of the chemical and physical compatibility of the solid form with the excipients to be used in the final formulation is required. Often called excipient compatibility screening. 

Over the years, various excipient compatibility methods have been developed to guide the selection of excipients. Excipient compatibility screening is generallyregarded as an essential part of the development process however, since real-time data are often not available during the initial stages of development, formulation scientists must employ accelerated stability studies on model formulations to estimate and predict long-term ambient stability. Such studies are costly and time consuming, and it is therefore desirable to minimise the number of studies performed. 

There are numerous ways to conduct excipient compatibility screening. In all cases, however, the basic method is the same - mix two or more materials together and monitor any subsequent reactions. In one type of study, drug-excipient mixtures are stored under accelerated stability conditions, such as binary blends, mini-formulations or statistically designed mixtures, and then assayed over time using liquid chromatography or spectrophotometry. A disadvantage of this technique is that it must be monitored for several weeks. Also, since the quality of the results depends on the precision of the assays, well-developed and sufficiently validated methods are required. 

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. 

To address the challenges in low-dose dmg product development, we recently initiated an excipient library approach, which follows the philosophy, an ounce of prevention is worth a pound of cure. The idea was to create a library of excipient-related information such as chromatographic background, stability, compatibility, and effect on dmg recovery and release. This library serves as a general tool for low-dose dmg development. Using the library, development teams are able to screen for the most appropriate excipients at the development planning/design phase on the basis of both formulation and analytical requirements. This approach aims to reduce analytical development difficulties where possible. 

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