Preformulation studies stages

Process validation is intended to show and document that the process described, when operating within the designated parameters, will produce product of the appropriate quality and demonstrate that the manufacturing process is under full control. Process validation should extend from laboratory-scale and preformulation studies (say to of production scale) to formulation to pilot-scale manufacture (say production scale) to full industrial-scale manufacture, with a clear, logical, and continuous path between these stages. The magnitude of scale-up at each stage should not normally exceed a factor of 10. 

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 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 ... 

From the summary data of the preformulation studies, scientists should obtain potential leads based on stability conditions designed in order to consider them for further development. The next stage of development, which we call formulation, should take into account all the parameters that may achieve one or more stable formulations for marketability with acceptable industrial stability. 

For development of a new chemical entity, the resolution of an optically active compound should be available in an earlier stage of the discovery process of the preformulation study. Selection of the enantiopure component or racemic mixtures to be a market product must be decided before patent application and IND submission. Heavy investment in the wrong chiral compounds may be lost if another enantiomer is to be developed. 

Hydrates and solvates can be prepared by crystallization in water or an organic solvent or by conversion of the anhydrous material through moisture or solvent adsorption. In quality control testing, hydrates or solvates are identified by the assay of water of crystallization or solvent found in the crystal. Water determination is achieved by Karl Fischer titration or a coulometric method or loss-on-drying by the USP method. In the preformulation study, the hot stage microscope is a useful simple technique. TGA can also be an informative tool, as shown in Figure 15. 

One of the major factors that often slows down preformulation studies is the availability of a sufficient quantity of a compound at this stage, especially if biopharmaceutic studies are conducted as a result, methods need to be devised that would utilize the smallest quantity of the substance this is amply emphasized throughout the testing phases in this book. Another factor that often slows down work at this stage is often misplaced importance on validated test methods and documentation while this is desired, the perennial shortage of manpower requires that some things take secondary importance. 

At the early stages of optimisation, preformulation studies are usually conducted to screen excipients or packaging materials and to select those compatible with the candidate drug, using accelerated stress testing procedures. More details about the preformulation techniques, which can be employed for compatibility studies, are discussed in Chapter 3. The importance of doing compatibility studies is for reducing the number of excipients and formulation options to test in further product optimisation studies. 

For the purposes of this discussion, we will assume that the project objectives are known, that priority has been established, that there are sufficient amounts of raw materials to carry out the investigations and that initial analytical procedures have been developed. A fundamental point that must be kept in mind throughout the early stages is that for New Chemical Entities (NCEs) the toxicological profile will not normally have been established at the preformulation stage. It is of paramount importance, therefore, to take all due precautions throughout the study. The preformulation study has several distinct phases (in approximate chronological order) ... 

A detailed description of most of the studies that form part of the preformulation stage are given elsewhere in this volume and will not be considered here. In addition, the importance of preformulation studies in the overall development of transdermal drug delivery systems has recently been excellently reviewed and discussed by Roy (1997). The only aspect of preformulation which is specific to and important for dermatological and transdermal formulations that will be discussed in depth in this chapter concerns drug delivery characteristics. 

Before process validation can be started, manufacturing equipment and control instruments, as well as the formulation, must be qualified. The formulation of a pharmaceutical product should be studied in detail and qualified at the development stage, i.e., before the application for the marketing authorization is submitted. This involves preformulation studies, studies on the compatibility of active ingredients and excipients, and of final drug product and packaging material, stability studies, etc. 

During the preformulation stage, the chemical and physical properties of the dmg moiety are studied exhaustively to ensure stabdity, safety, bioavadabdity, and therapeutic efficacy. Tablets are produced directly by compression of powder blends or granulations, which include a small percentage of fine, particle-sized powders. 

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... 

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