Preformulation studies development

Other products related to the pharmaceutical business include diagnostic products, medical devices, and radiopharmaceuticals. Although they should have preformulation studies developed on an individual basis, they will not be discussed in this chapter. 

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. 

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. 

Graffner, C., M. E. Johansson, M. Nicklasson, and H. Nyqvist. 1985. Preformulation studies in a drug development program for tablet formulatiodsPharm. Sci74 16-20. 

In order to develop a robust formula for a drug product (pharmaceutical dosage form) it is important to understand the chemical and physical properties of the API in conjunction with excipients that may be used to create the most stable product formula in terms of activity and potency. An outline of possible preformulation studies that should be conducted to ensure a proper and complete understanding of the chemical and physical properties of the API is presented in Table 3. 

With the results of the preformulation studies, the formulation scientist can begin to address some of the specific questions pertaining to the development of the final formulation. The state of the dosage form is selected. The inactive ingredients in the formulation, excipients, which promote stability of the final product, are screened. Finally, supportive accelerated stability studies are conducted to aid in the selection of the final formulation. 

Characteristics of the product and functions in early clinical studies are the driving force for initial product development. Often, there is a nominal knowledge of the API characteristics at such an early juncture. Preformulation studies provide attributes such as solubility, effects of pH, and predict sensitivities to environmental conditions. Solubility, along with pharmacologic characteristics, dictates the volume in the product container. Sensitivities to environmental conditions include temperature, light, oxygen, and contact surfaces. Specific to lyophilized preparations, there is also the potential for degradation via hydrolysis reactions when in the presence of water. Each of these... 

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 ... 

Before preformulation studies are undertaken, two-way technical communication between the manufacturers of the API (laboratory and plant) and the pharmaceutical product development laboratories must be established (Fig. 1). It should start early and be maintained through-out the product and process development program. 

Following successful preformulation studies, the API is transferred to the formulations laboratory for preliminary product design and development studies. In most cases, the drug is mixed with an appropriate diluent or... 

The focus of this chapter is a discussion of various preformulation studies related to tablet dosage form development. The physicochemical properties of interest can be divided into two broad categories (r) molecular properties which are intrinsic to the drug substance and cannot be modified without chemical modification of the API. and ii) physical properties, which are amenable to modification to suit the needs of formulation. The molecular and the physical properties are listed in Table 1. 

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