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FORMULATION DEVELOPMENT/INSTRUMENTATION
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Solid State Considerations for Early Development
Jeffrey Stults, PhD
Senior Scientist Genentech, Inc.
“The enemy of a good plan is the dream of the perfect plan.” Carl von Clausewitz
Introduction
Solid form screening has become an important activity in drug development. The initial screening activity is designed to find an acceptable physical form of the active pharmaceutical ingredient (API) for development.
This article attempts to describe a rational process, although imperfect, for form screening suitable for early development. It is an iterative process with screening activities becoming more comprehensive as more material and resources become available. Each portion of the screening process is designed to answer the key questions associated with the form for the next development stage. Its goal is not to find the perfect form but to find an acceptable form for development.
Screening Considerations
Submitted: 11/17/2014 Accepted for Publication: 12/01/2014
Stults J. Solid state considerations for early development. Am Pharm Rev. 2015;18(1):54-57.
There are 4 basic approaches to developing a suitable form. They are development of (a) the neutral form (eg, free acid or free base) either as a non-solvated or solvated form; (b) a salt of the API, if possible, also as the non-solvated or solvated form; (c) of a cocrystal; or (d) amorphous material, either as pure amorphous API or as a solid dispersion with an appropriate carrier.1,2
Many properties of the API are affected by the form chosen.3 Among
these properties are solubility, hygroscopicity, color, melting point, dissolution rate, flow, filterability, compressibility, and excipient compatibility. The key criteria for form selection are: (a) exposure— typically related to dissolution rate and solubility, (b) stability—both chemical and physical as drug substance and drug product, and (c) ease of manufacture.
The preferred order of form for development is the free form—first provided the free form provides sufficient exposure for the intended studies. A salt form is next preferred since it may add complexity to the process. The polymorph screen of the free form can be delayed if stability or pH solubility problems are expected and salt selection can be started instead. Generally both polymorph and salt selection are conducted concurrently if material is available. The desire is to develop a crystalline material which is typically the most thermodynamically stable form—unless there are stability problems, or absorption is solubility-limited, or a higher rate of dissolution is needed (higher Cmax
or shorter Tmax ). Cocrystal screening is becoming more common although there is only 1 known cocrystal commercial product, 54 | | January/February 2015
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