Preformulation Development

Finally, the last step in the preformulation development process is to test the candidate formulations that exhibited the greatest overall stability, using microcalorimetry. The true test of the procedure summarized in Figure 13.7 is to... 

TABLE 15.2 Bioanalytical Methods Used to Evaluate Initial Preformulation Development... 

Bedu-Addo, E., Moreadith, R., Advant, S., Preformulation development of recombinant pegylated staphylokinase SY 161 using statistical design, AAPS Pharm., Sci. 4, article 19, 2002, www.aaps.org.. 

The therapeutically active dmg can be extracted from plant or animal tissue, or be a product of fermentation (qv), as in the case of antibiotics. Frequentiy, it is synthesized and designed to correlate stmcture with therapeutic activity. Pharmacologic activity is first tested on laboratory animals. When the results ate encouraging, physical and chemical properties are determined in the so-called preformulation stage, and analytical procedures are developed for quahty control (see Qualityassurance/qualitycontrol). 

A prototype system implemented with the Formulogic shell has recently been reported by Pfizer [21]. The system has been designed to use preformulation data on new drugs and recommend early development formulations, predict product properties, and select processing conditions suitable for scale-up. 

The system developed by personnel at Sanofl uses the Formulogic shell with specific preformulation data on the drug. The system recommends one first-pass clinical capsule formulation with as many subsequent formulations as desired to accommodate an experimental design [24]. An example of a formulation proposed for naproxen at a dose of 500 mg is shown in Table 28.2. In addition to the formulation the system provides advice on the milling of the drug, the process to be used for blending, and details of the capsule shell. 

The other main approach to solubility is to measure the concentration of the drug substance after an equilibrium has been reached with the solvent in question. This work is also conducted very early during the development process, normally at the stage of preformulation characterization [7]. A full discussion of the various aspects of solution theory is beyond the scope of the present chapter, but it is available [68]. Only a few salient points will be addressed in the following paragraphs. 

Since an understanding of the nature of water sorption by materials is of extreme interest to the formulator, an evaluation of the degree of hygroscopicity associated with a given material is crucial to the development process. A systematic approach for these types of studies has been outlined, in which the kinetics of water adsorption can be deduced [84]. This work should be performed at the preformulation stage, where the effect of water on the various components (and mixtures of these) needs to be addressed prior to any final decision as to the formulation composition [85]. It would be far better to discover any... 

Thermal methods can be extremely useful during the course of preformulation studies, since carefully planned work can be used to indicate the existence of possible drug-excipient interactions in a prototype formulation [2]. During the course of this aspect of drug development, thermal methods can be used to evaluate compound purity, polymorphism, solvation, degradation, drug-excipient compatibility, and a wide variety of other desirable characteristics. Several recent reviews have been written on such investigations [2-6]. 

Powder flow is most frequently thought of as relevant to formulation development, and there are numerous references attempting to correlate any one of a number of measures of powder flow to the manufacturing properties of a formulation [34—40]. In particular, the importance of physical properties in affecting powder flow has been well documented. Research into the effect of the mechanical properties on powder flow has, however, been very limited. It is, of course, important to be able to determine and quantitate the powder flow properties of formulations. It is of equal importance, however, to determine the powder flow characteristics of bulk drug early in the development process (preformulation phase). Often, the preformulation or formulation scientist is constrained by time, materials, and manpower. Yet certainly the preformulation studies carried out should be meaningful. Well-defined experimental methods and procedures should be used the information generated should be reproducible and permit useful predictions to be made. 

In a more traditional pharmaceutical setting, this characterization would be done during preformulation studies. With the availability of automation and the ability to conduct most of these experiments with small quantities of material, more preformulation activities are being shifted earlier into drug discovery. Recently, Balbach and Korn37 reported a "100 mg approach" to pharmaceutical evaluation of early development compounds. Additional absorption, metabolism, distribution, elimination, and toxicity38 screens may also be conducted at this stage. 

Abrahamsson, B. and Ungell, A.L., Biopharmaceutical support in formulation development, in Pharmaceutical Preformulation and Formulation, Gibson, M., Ed., CRC Press, Boca Raton, FL. 

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 studies incorporate API qualification and evaluation of key excipients. Studies should incorporate studies of combinations of API and excipients and a rationale developed for the levels of various excipients chosen. Interactions between the API and excipients are expected and should not form the basis of altering the choice so long as data can be collected to show that the API is available through the shelf-life. 

A pilot production is at about a lOOx level in general, the full scale-batch and the technology transfer at this stage should comprise preformulation information, product development report, and product stability and analytical methods reports. This is the time to finalize the batch production documentation for the lOOx level. The objectives of prevalidation trials at this stage are to qualify and optimize the process in full-scale production equipment and facilities. 

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