Form…..Formation…..Formulation…..The 3 “Fs”
Preformulation, or the physicochemical characterization of your Active Pharmaceutical Ingredient (API) in light of the intended route of administration and dosage form, is an important phase pharmaceutical development. Preformulation activities typically start a the candidate selection stage and continue into the clinical phase I, with optimization of the formulation and further characterization of the API taking place in, or after, phase II clinical studies. In the initial phase, the appropriate solid form is selected based on a number of criteria such as chemical and physical stability, dissolution and solubility in relevant biological media. Physiochemical tests carried out during the initial phase enable sound decisions for the solid form selection that will maximize the probability of the API’s success in preclinical studies and which are essential to the establishment of strong intellectual property positions. In these studies it will become clear whether certain criteria mentioned in your Target Product Profile are going to be met.
Probably the most critical and difficult phase for any New Chemical Entity (NCE) to pass is the preclinical toxicology phase. At this phase, 50% of the NCEs fail for toxicity reasons and another 15% fail for lack of bioavailability and short half-life. Strict regulatory requirements for toxicity studies demand an exposure in test animals of close to 100 fold the EC50 value. For the general poorly soluble APIs that come out of discovery achieving such exposure levels is a real hurdle. Your choice of solid form combined with appropriate preclinical formulation development could make the difference between failure and success. The salt, cocrystal or amorphous dispersion you are using for your preclinical research may not be your final solid form for the commercial product. For example, a highly hygroscopic or deliquescent salt form of your API may be very soluble and can be used to demonstrate safety at high exposure levels in animals but such a salt will never be used as final form for a commercial formulation.