Because polymorphism can have an effect on so many aspects of drug development, it
is important to fix the polymorph (usually the stable form) as early as possible in the development cycle and probably before campaign 3. The FDA has produced guidance for industry: ANDAs: Pharmaceutical Solid Polymorphism Chemistry, Manufacturing, and Controls Information (http://www.fda.gov/cder/guidance/7590fnl.htm). Raw et al. (2004) have reported this in the literature, but the reader should consult the FDA Web site for the most up-to-date guidance. While it is hoped that the issue polymorphism is resolved during prenomination and early development, it can remain a concern when the synthesis of the drug is scaled up into a larger reactor or transferred to another production site. In extreme cases and despite intensive research, work may have only produced a metastable form and the first production batch produces the stable form. Dunitz and Bernstein (1995) have reviewed the appearance of and subsequent disappearance of polymorphs. Essentially, this describes the scenario whereby, after nucleation of a more stable form, the previously prepared metastable form could no longer be made. The role of related substances in the case of the disappearing polymorphs of sulphathiazole has been explored (Blagden et al., 1998). These studies showed that a reaction by-product from the final hydrolysis stage could stabilize different polymorphic forms of the compound depending on the concentration of the by-product. Using molecular modeling techniques, they were able to show that ethamidosulphthiazole, the by-product, influenced the hydrogen bond network and hence form and crystal morphology. In the development of a reliable commercial recrystallization process for dirithromycin, Wirth and Stephenson (1997) proposed that the following scheme should be followed in the production of Candidate Drugs . 1. Selection of the solvent system 2. Characterization of the polymorphic forms 3. Optimization of process times, temperature, solvent compositions, etc. 4. Examination of the chemical stability of the drug during processing 5. Manipulation of the polymorphic form, if necessary While examples of disappearing polymorphs exist, perhaps more common is the crystallization of mixtures of polymorphs. Many analytical techniques have been used to quantitate mixtures of polymorphs, for example, XRPD has been used to quantitate the amount of cefepime: 2HCl dihydrate in cefepime, 2HCl monohydrate (Bugay et al., 1996). As noted by these workers, a crucial factor in developing an assay based on a solid-state technique is the production of pure calibration and validation samples. Moreover, while the production of the forms may be straightforward, production of homogeneously mixed samples for calibration purposes may not be so. To overcome this problem, a slurry technique was employed, which satisfied the NDA requirements, to determine the amount of one form in the other. The criteria employed are as follows: 1. A polymorphic transformation did not occur during preparation or analysis. 2. A limit of detection of 5% (w/w) of the dihydrate in monohydrate. 3. Ease of sample preparation, data acquisition, and analysis. 4. Ease of transfer to a quality control (QC) environment. Calibration samples were limited to a working range of 1% to 15% w/w, and to prepare the mixes, samples of each form were slurried in acetone to produce a homogeneous mixture of the two. With respect to solid dosage forms, there have been a few reports on how processing affects the polymorphic behavior of compounds (Morris et al., 2001). For example, the effect of polymorphic transformations that occurred during the extrusion-granulation process of carbamazepine granules has been studied by Otsuka et al. (1997). Results showed that granulation using 50% ethanol transformed form I into the dihydrate during the process. Wet Preformulation: An Aid to Product Design 209 granulation (using an ethanol-water solution) of chlorpromazine hydrochloride was found to produce a phase change (Wong and Mitchell, 1992). This was found to have some advantage since form II (the initial metastable form) was found to show more severe capping and lamination compared with form I, the (stable) form produced on granulation. Using a range of compounds, Wikstrom et al. (2008) have studied factors that influence the anhydrateto- hydrate conversion during wet granulation and concluded that the transformation was a function of such things as the compounds solubility, surface properties, seeds, and the shear forces involved in wet granulation. However, even this paper noted that better models were needed to understand the complexities of the transformations. Solvate formation may have some advantages. For example, Di Martino et al. (2007) showed that the desolvated dioxane solvate of nimesulide had better tableting properties than the known polymorphs of the compound, which appears to represent a viable method of improving the compression properties of drug substances. Polymorphism is not only an issue with the compound under investigation, that is, excipients also show variability in this respect. For example, it is well known that the tablet lubricant magnesium stearate can vary depending on the supplier. In one study, Wada and Matsubara (1992) examined the polymorphism with respect to 23 batches of magnesium stearate obtained from a variety of suppliers. Using DSC they classified the batches into six groupsinterestingly, the polymorphism was not apparent by XRPD, IR, or SEM observations. In another report, Barra and Somma (1996) examined 13 samples of magnesium stearate from three suppliers. They found that there was variation not only between the suppliers but also in the lots supplied by the same manufacturer. It is well known that polymorphism is a function of temperature and pressure, thus under the compressive forces that compounds experience under tableting conditions phase transformations may be possible. However, Nemet et al. (2005) have sounded a note of caution when conducting analysis of compressed samples. They reported that DSC measurements tended to amplify the transformation of form B to form A of famotidine. SOLUTION FORMULATIONS Development of a solution formulation requires a number of key pieces of preformulation information. Of these, solubility (and any pH dependence) and stability are probably the most important. As noted by Meyer et al. (2007), with over 350 parenteral products marketed worldwide, these probably represent the most common solution formulation type. The principles and practices governing the formulation development of parenteral products have been reviewed by Sweetana and Akers (1996). Strickley (1999, 2000, 2001) has produced a useful series of papers detailing the formulation of a large number of compounds delivered by the parenteral route. A further review by Strickley (2004) has detailed solubilizing excipients for both oral and injectable formulations. Rowe et al. (1995) have described an expert system for the development of parenteral products (see also chapter 9). Solubility Considerations One of the main problems associated with developing a parenteral or any other solution formulation of a compound is its aqueous solubility. For a poorly soluble drug candidate, there are several strategies for enhancing its solubility. These include pH manipulation, cosolvents, surfactants, emulsion formation, and complexing agents; combinations of these methods can also be used (Ran et al., 2005). More sophisticated delivery systems, for example, liposomes, can also be considered.