Tablet formulation development is a stylized process. Each formulator uses their own methodology. Some use the systematic Design of Experiments (DOE) approach, some test one variable at a time, and many use a combination of the two. However, all formulators need a methodology that gives them reliable and useful information to identify problems before tablet manufacturing begins.
New formulators can find it difficult to know where to start in the development process. A rigorous and creative stepwise approach will help a formulator identify issues in an active pharmaceutical ingredient (API) that would hinder its processability. Following an approach like the one outlined below can help your formulation become a great product.
Testing the API
The first and most crucial step of developing a formulation is to determine how the API behaves. Some formulators do minimal studies on the API alone or skip this step entirely. However, it’s important to characterize the API so the correct excipients can be identified based on the API’s behavior.
The four main API features to examine are:
- Physical characteristics
The best place to start when characterizing an API is with compatibility and physical characteristics. These studies are the most time-consuming and can be run concurrently. Compatibility studies usually run from one to four weeks. In this step, a formulator is evaluating the API and how it interacts with standard excipients or excipients that are necessary to adhere to the target product profile (TPP). For example, if the TPP calls for an extended-release profile, the API needs to be tested for compatibility with controlled-release polymers. Compatibility studies are usually conducted as a binary mixture of the API with each excipient to determine whether any of the materials are incompatible with the API.
Compatibility studies also should include the neat API powder as a control. This will give the formulator information on the mechanism of degradation and which storage conditions are appropriate. For example, a neat API that is stored at elevated stress conditions (40°C/75% relative humidity) can be a complex endeavor because accelerated conditions usually don’t reflect what happens in real time. Are accelerated conditions yielding acceptable data?
Conducting morphology, crystallinity, and particle size studies in addition to compactibility and flowability is strongly recommended to determine physical characteristics. Understanding the effects of irregularly shaped particles and highly ordered crystalline structures will help determine whether a granulation step is needed to improve flow or the solubility of the API.
Compactibility studies are best conducted on an instrumented single-station press. Using a single-station press, or a rotary press that can operate in single-station mode allows the formulator to conduct strain rate and dwell time studies to understand consolidation of the API. For example, if an API is highly compactible, the formulator knows they can use significantly less binder.
Flowability studies can be as simple as putting the API into a glass vial and watching how it flows. Establishing the angle of repose, Carr index, and Hausner ratio are other easy tests. Another simple test is evaluation on a Flodex or another flow-through-orifice apparatus. Other flowability studies are more analytical and involve instrumentation such as a powder flow rheometer. These instruments help the formulator understand the angle of internal friction and wall friction based on material of construction. In assessing flowability, the formulator is looking for how well the powder flows as well as other problematic characteristics such as tendency to bridge, rathole, or agglomerate.
There’s rigorous debate among formulators about whether determining the characteristics of an API is necessary. However, understanding the material properties of the API alone will determine which excipients and processes are needed to overcome significant deficiencies of the API or to achieve the TPP. Testing the API provides a starting point before evaluating its interactions with other materials.
Adding the Excipients and Process Selection
After the API has been evaluated the formulator can add excipients to develop the formulation. Any excipient added should be in service to the API or the TPP. In other words, the data gathered while testing the API should inform the decision on which excipients and at what concentration to start the formulation development. Each excipient should be chosen to overcome the issues identified when testing the API or to achieve the TPP.
In this phase of development, it’s important for the formulator to have more than one formulation to evaluate. There’s a good chance a formulation will fail at some stage, so having more than one available for testing means not having to go back to the beginning of the process.
Tests during this phase should include evaluating a blending process, blending order of addition, granulation method if needed, and the tableting process. Once the formulator has prototype formulations and processes, they should start short-term stability studies that last no longer than three to six months. This is the stage in which to gauge process development and identify tablet defects like sticking and picking or coating issues like tablet chipping. All the tests help set parameters for scalability and increase the odds of the formulation succeeding in clinical batch manufacturing, validation, and commercial-scale production.
Troubleshooting Is Reactive – Be Proactive
Formulation development is an iterative and often frustrating process. Many formulators spend a lot of time troubleshooting later in the development process. Troubleshooting is reactive, with the formulator responding to an issue he hadn’t anticipated.
A stepwise approach, on the other hand, allows you to be proactive. For example, if compatibility studies are not completed, you might find a prototype formulation is not stable over a three to six-month stability study. Troubleshooting the issue will lead to many questions: What is causing the instability? Which excipient or combination of excipients is the culprit? Could the issue be the API in a specific storage condition? A proactive approach earlier in R&D will give you the best chance to succeed.
Using a less organized approach can lead to wasted time and money as a formulator tries to determine where in the process the formulation began to experience problems. The data generated by a stepwise approach is crucial to pinpointing where problems began, saving valuable resources and accelerating product development.
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