Stability Issues Related to Soft Gelatin Capsule Development

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Stability issues are a challenge and never ending concern for formulators. The reactivity of formulation depends on many factors, but it is generally recognized that labile drugs in aqueous forms are sometimes the worst case scenario, and this should be a true statement for the development teams that work with softgel development. Although product development has been described by many authors as a cycle, we would refer to it as a tower, where pillars are the preformulation phase. Most of the reference information about the API(s) and the excipients are gathered at this stage in order to guide the next steps and to build the product documentation for filing. What was not disclosed is that based on that definition, preformulation would be highly consuming in both time and resources in order to guarantee success at the final product. It was only stated many years later by introducing the QbD concept!

It would help to illustrate the concept, thinking about the preformulation phase as the way to solve the incognita ABC through the equation: A+AC+B+BC=ABC, being A the fill formulation, C the stability conditions (temperature, humidity, light), B the gelatin formulation and ABC the softgel product. In the same way, since the gelatin softgel is a primary packing for the medicine, it would also help to apply the same reasoning of packing development to formulation development. Then, why is it not the same criteria applied to gelatin formulations since they are the primary packing of the drug? Using the same packaging, would be a particular gelatin formulation proper to any climate conditions?

Formulation of pharmaceutical products has been considered a tailor-made approach for each product and according to this, defining a formulation guide is somewhat controversial. However, to establish a guide with multiple considerations on formulation is a great help as the first step to discard predictable incompatibilities and to avoid the most common formulation non-compliances. Here, a starting point would be to define the complexity of the system: Is a same gelatin formulation indicated to formulate both hydrophilic and lipophilic fill contents? On the other hand, some incompatibilities are difficult to detect at a lab. Usually, there is a constraint to obtain capsules at a small scale, to test the system as a whole and evaluate migration phenomena: one of the causes of the most of the defects in softgels (dissolution non-compliance, opacity, blooming, etc). Then, the question is what to do? What are the lab tests and the analytical tools that help to make it easier? Shortcuts are highly desirable therefore we will discuss them in our upcoming webinar.

What about the timings? From the beginning we anticipated that preformulation in spite of being the safe side, is a time consuming phase. In this regard, one of the questions needed to be considered would be: In a project framework, how much time is foreseen to cover difficulties in preformulation? Here, using a weighted punctuation for the product complexity to estimate formulation times would be a recommended approach. What about the scale? Is there any way to make preformulation at lab conditions or will final results depend on final capsules? Here, there is another concern in the way to make preformulation as profitable as it could be and that is to determine if lab tests correlate well with pilot scale (adding more work!). In general, it could be reliable at least to test the excipients, when process parameters are kept as controlled as possible at a lab scale.

What about the results? We started the QbD framework some years ago and what we´ve learned about gelatin preformulation is the importance of consolidating the lessons, building the decision diagram and feeding the formulation bank. This includes the criteria for the selection of a gelatin formula or another, on a general basis as well as in some specific cases. The QbD approach offers an exploration space that covers the most relevant aspects of development. It is important to bear in mind that this approach doesn´t guarantee that you don´t have to go back during the process, but if it happens, you will certainly return with qualified information. This gives you a criteria of what to do and what not to do, as well as the knowledge of what are the most probable causes of non-compliance. In brief, it is for sure a matter of time: the saved time from non-compliances and reformulation!

Finally, as the purpose of this space is to share knowledge and experiences, we would like to hear from you regarding the questions stated above as well as your own questions. To learn more insights on this matter join us in our upcoming webinar on Application of QbD principles in the development of the gelatin shell formulation of softgels.

Register now here.

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