Preformulation stage physicochemical properties

Early on in product development, the potential for the successful development of a solid oral dosage form is assessed, based on the physicochemical properties of the API (1). Prior to solid dosage form development, it is necessary to anticipate the physicochemical properties that can have a major influence on product manufacture and performance. The early development (preformulation and early formulation development) studies should focus on these properties so as to avoid problems at later stages of development. While the molecular properties dictate the intrinsic solubility and the chemical stability of the compound, by controlling the physical form of the compound and by modifying physical properties (e.g., particle size), the dissolution rate can be enhanced with the potential for improving bioavailability. This chapter will focus on physical properties including particle characteristics, and most importantly, the physical form (i.e., solid state) of the API. 

This level of preformulation should be initiated in the beginning of the development cycle. The data consist of physicochemical properties of the chemical substance and analytical properties useful in the development of analytical methods, the evaluation of material quality, and testing for the acceptance of the formulation developed. In the early stage of development, the synthetic scheme is developed and the material available for preformulation may be limited. Thus the lack of supply quantities may affect the quality of data obtained. As the development cycle is pushed forward and the drug availability improves, data should be updated or refined with the use of more complicated and accurate methods. Part 1 of the preformulation report may be published before the establishment of specifications. The portion of this report consisting of analytical data may be known as an analytical profile in some organizations. 

During the preformulation and formulation stages of a parenteral dosage form, the physicochemical properties and excipient compatibility of the pharmaceutical active ingredient (API) should be thoroughly evaluated. The test method requirements are similar to those for oral dosage forms. 

Polymorphism has received widespread general interest in pharmaceutical drug development because of its impact on the physicochemical properties of APIs and also because of their economic significance. It is considered mandatory to perform a thorough and exhaustive sohd-form screening of all possible polymorphs of a lead drug molecule at the preformulation stage. The purpose is to discover as many solid forms as possible and to identify the most suitable... 

At an early stage during the preformulation program for the candidate, particularly for those with unfavorable physicochemical and physicomechanical properties as a free acid or free base, it is normal procedure to investigate a suitable range of potential salts. Typically 4-6 different salts are evaluated, if they can be isolated. Often the properties of the free acid (or free base) are hardly satisfactory and it is recommended that it is included in the comparative exercise using a battery of tests (see Section V). If a parenteral dosage form is intended and the properties of the free acid or free base are better than any of the salts, it is often possible to prepare a salt in situ in the liquid vehicle. 

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