Preformulation testing

Preformulation testing provides a basic dossier on the compound and plays a significant role in identifying possible problems and suitable approaches to formulation. Such dossiers already exist for the common excipients. The requirement for aqueous solubility is paramount and preformulation can identify salt forms that are appropriate for further development. Stability and solubility studies wiU indicate the feasibility of various types of formulation such as parenteral liquids and their probable shelf lives. Similar information can be garnered for solid products from the solid physical properties. By performing these studies on a series of candidate compounds, the optimum compound can be identified and further biological and chemical studies guided to provide the best results. 

Preformulation testing for insoluble compounds has many unique aspects. Special techniques need to be applied to study the physicochemical properties and to understand potential problems so that the correct foundations can be laid fora successful formulation andrttotoed products ultimately. 

Drug solubility is one of the physicochemical parameters that receives lots of attention during preformulation testing. In the initial stages, solubility studies are usually kinetically determined, where the drug is placed in contact with the solvents and then the solubility is assessed using turbidometric methods almost instantaneously. 

Based on the major goal of preformulation—identification of possible failure in future development—numerous studies are performed to fully characterize prospective drug candidates. The major analytical technique in each preformulation group is liquid chromatography. Ninety percent of all analytical equipment in preformulation groups are HPLC systems equipped with UV and MS detection systems. HPLC is a fast and reliable method for concentration and identity determination by UV and/or MS detection, respectively. The type of HPLC methods differ based on the specific preformulation tests that will be described below. 

Figure 9 Apparatus for preformulation testing of the kinetics of photostability of drugs in solution. Abbreviations V, reaction vessel ...

Jacobs, A.L. Determining optimum drug/excipient compatibility through preformulation testing. Pharm. Manuf. 1985, 2 (6), 43. 

Preformulation testing of the specific API of interest and key excipients to be used in the product design stage, alone and in combinations with the API, should be included as a preliminary first step in the product and process development sequence. A simple check list of items worth consideration in preformulation studies with APIs and important or critical excipients is provided as follows ... 

Akers MJ. Preformulation testing of solid oral dosage forms. Methodology, management and evaluation. Can J Pharm Sci 1976 11 1-10. 

Preformulation testing encompasses all studies enacted on a new drug compound in order to produce useful information for subsequent formulation of a stable and biopharmaceutically suitable drug dosage form. 

A number of other studies can be performed on a candidate drug to determine other important solid-state properties, for example, particle size, powder flow and compression and polymorphism. Therefore, when a sample undergoes initial preformulation testing the following parameters should be noted particle size, true, bulk and tapped density, surface area, compression properties and, powder flow properties. Some of these factors will be discussed in this chapter others, however, are dealt with in more detail in Chapter 11 on Solid Oral Dosage Forms. 

An extremely fruitful area of research and publication in the field of preformulation testing by LC is that of partition coefficient or HpophiHcity determination. Several standard procedures are available, including the relationship between partition coefficient and reversed-phase retention behavior (logP versus log ). Many variations in method and calculations have been proposed, such as comparison with an internal standard partitioning, variation in organic content of the mobile phase for the retention model, and rudimentary assay of organic and aqueous phase in the shake-flask experiment by LC. 

During bulk drug stability and preformulation testing, preliminary formulations and processes are developed that are first stability tested on a shortterm, accelerated basis. Drug product intended for clinical use after IND approval must be stability... 

Table 8.1 Some techniques commonly employed during the preformulation testing phases to characterise drug substances...

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