Pharmaceutical development preformulation

Winnike R. Solubility Assessment in Pharmaceutical Development, Practical Considerations for Solubility Probling and Solubilization Techniques. AAPS Short Course on Fundamentals of Preformulation in Pharmaceutical Product Development, Nashville, TN, Nov. 5, 2005. 

In the pharmaceutical industry, preformulation is not generally carried out by one department alone. This activity integrates efforts of well-coordinated tasks among many research teams analytical research, basic pharmaceutics, quality control, dosage forms development, and others throughout the... 

The cycle of pharmaceutical development with stages and milestones such as discovery, IND, NDA, and market introduction is discussed in this chapter. The discussion also demonstrates the fit of the preformulation into the total development activities. The contents of the preformulation reports illustrated are comprehensive in comparison with the conventional definition in preformulation. Although basic pharmaceutical principles and theory are not included in this chapter, literature references are provided. The expedience of providing documents in one volume (with three subparts) for the formulator is emphasized. 

In this chapter, pharmaceutical and health-care products, such as prescription drugs, generic drugs, OTC products, animal health products, dietary supplements (vitamins and herbal drugs), and biotechnology-derived products, are discussed in relationship to the format of preformulation reports. Topics of the preformulation study are discussed in detail. Models for some of the reports are provided in the hope that the pharmaceutical development team will devise an individual report format based on particular needs and resources. Analytical techniques useful for preformulation and regulatory conformity or requirements relative to product registration processes are also enumerated. 

Candidate drugs being evaluated for development are often one of a series of related compounds that may have similar chemical properties, that is, similar paths of degradation may be deduced. However, this rarely tells us the rate at which they decompose, which is of more importance to pharmaceutical development terms. To elucidate their stability with respect to temperature, pH, light, and oxygen, a number of experiments need to be performed. The major objectives of the preformulation team are, therefore, to identify conditions to which the compound is sensitive, and to identify degradation profiles under these conditions. 

Another potential barrier is any overlapping expertise there may be in Research and Development groups. For example, overlap may occur between Preformulation in Pharmaceutical Development and Physical Chemistry in Research, or between Biopharmaceutics in Development and Drug Metabolism in Research. In these cases, it is important to clarify and agree which group does what activity. 

For pharmaceutical development, risk may be associated with the technical challenges anticipated in developing a novel or complex drug delivery system or manufacturing process. Information from early preformulation and biopharmaceutics studies should indicate the potential problems for drug delivery, formulation development and manufacture. 

With these limitations in mind, this chapter concentrates on the specific considerations which are fundamental to the development of pharmaceutical dosage forms designed for application to the skin. Many of the early pharmaceutical development stages for these dosage forms, such as preformulation and drug substance stability, are common to dosage forms designed for other routes of delivery. These have been fully discussed elsewhere in this volume and will not be discussed in depth here. 

This chapter will discuss the role of the analytical chemist in the preformulation process and highlight the methods that will need to be developed, validated and utilized to support these studies. An assortment of analytical techniques is needed to measure a number of critical quality attributes of the new molecular entity such as solubility, purity, and crystalline habit. The methods will be used to make important decisions such as the choice of salt form, or which sohd oral dosage form has the best probability of providing adequate exposure in an early phase clinical study. These analytical tools are critical to the decision that a pharmaceutical development organization uses to evaluate the first round of solid dosage form development prior to the availability of clinical data. 

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. 

He has been responsible for pharmaceutical product development from exploratory development, preclinical, preformulation, and drug delivery platform technologies, formulation, process, and scale-up manufacturing toward commercialization. 

Analytical testing (preformulation, stability, product release) is a core component of pharmaceutical operations from early R D through manufacturing of the commercial product. The original analytical methods are usually developed by the pioneer pharmaceutical firm and transferred to the provider. In some cases, the early methods are only preliminary methods and are not sufficiently robust to test the quality of downstream (clinical, commercial, and line extension) products and facility quality practices (cleaning validation). In those situations, the supplier is often asked to develop new methods, and in some cases those methods are transferred back to the client. In either scenario, the transfer of validated analytical methodology consists of the following four main tasks [52] ... 

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. 

Garg, S., Kandarapu, R., Vermani, K., Tambwekar, K. R., Garg, A., Waller, D. P., and Zaneveld, L. J. (2003), Development pharmaceutics of microbicide formulations. Part I Preformulation considerations and challenges, AIDS Patient Care STDS, 17,17-32. 

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