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  • 1. 1Form Selection of PharmaceuticalCompoundsAnn W. Newman and G. Patrick StahlySSCI, Inc., West Lafayette, IndianaI. INTRODUCTIONThe drug development process involves a number of activities which are carriedout simultaneously, as shown by the oversimplied depiction in Fig. 1. Once amolecule is discovered that has desirable biological activity, the process of creat-ing a pharmaceutical drug product from this molecule begins. As toxicology andefcacy studies are undertaken, methods for manufacture of the active moleculeand for its delivery in therapeutic doses are sought. Critical to the latter effort isnding a form of the active molecule which exhibits appropriate physical proper-ties. The form ultimately selected, called the active pharmaceutical ingredient(API), or drug substance, must be stable and bioavailable enough to be formulatedinto a drug product, such as a tablet or suspension. This formulation must beeffective at delivering the active molecule to the targeted biosystem. This chapter describes methodology useful in selection of the appropriatesolid form of a drug substance for inclusion in a drug product. Form selectionis commonly considered among the primary goals of a preformulation study.However, the investigative techniques discussed herein also have application inearly drug substance and drug product development activities (shown by the cir-cled area in Fig. 1). Solid form selection involves the preparation and property evaluation ofmany derivatives of an active molecule. Drug substance properties of importancein the drug development process may be categorized as shown in Table 1. Theseproperties depend on the nature of the drug substance and the nal formulation.Many bioactive organic molecules contain ionizable groups such as carboxylicCopyright 2002 by Marcel Dekker. All Rights Reserved.

2. Fig. 1 The drug development process. acid or amino groups. Reaction of these compounds with acids or bases produce salts, which have much different physical properties than the neutral parents. A single molecular entity, be it a salt or a neutral molecule, often exists in multiple solid forms, each of which exhibits unique physical properties. The properties of many such forms need to be evaluated relative to the intended formulation. A lyophilized product that will be dissolved and injected needs to be chemically stable in the dry state and adequately soluble in the carrier. On the other hand, the drug substance in a tablet formulation needs to be processable, chemically stable, and physically stable in the dry state, as well as having adequate solubility for delivery.Form selection activities should be started as early in the development pro- cess as material availability allows. Salt selection, including preparation and eval- Table 1 Some Important Properties of Drug Substances Bioavailability Chemical and physical stability Processibility Dissolution rate Excipient compatibilityColor Solubility Hygroscopicity Compactibility Toxicity Oxidative stabilityDensityPhotostability Ease of dryingThermodynamic stabilityFilterabilityCrystal form Flowability Hardness Melting point Particle sizeCopyright 2002 by Marcel Dekker. All Rights Reserved. 3. uation of samples, and polymorph screening can be carried out with as little ashalf a gram of active compound. Results of form selection include informationthat can be used in planning the nal step of the manufacturing process (oftencrystallization) as well as information that is critical to formulation development. The nature and extent of work to be performed during development canbe modeled after the draft International Committee on Harmonization (ICH) Q6Adocument on specications, which can be found on the Food and Drug Adminis-tration (FDA) website ( This document outlines the speci-cations needed for a New Drug Application and contains several decision treesto guide the selection of specications. The Q6A decision tree 4 (Fig. 2) describesFig. 2Flow chart 4 from the ICH Q6A document ( 2002 by Marcel Dekker. All Rights Reserved. 4. Fig. 2 Continued methods for the study of solids for a polymorph screen as well as characterization of the drug substance in the drug product. Other decision trees have also been reported in the literature (1).In this chapter we describe the form selection process. A short review of the analytical techniques commonly employed is followed by sections covering salt and solid form selection. Form selection should be approached in a planned, rational manner, but it is important to realize that not all compounds will allow adherence to a single experimental plan. The exercise is a scientic one, and it will yield the best results only if carried out with judgment and exibility. II. ANALYTICAL TECHNIQUES A number of analytical techniques are commonly used in form selection studies. Various publications (24) and books (5,6) describe physical characterizationCopyright 2002 by Marcel Dekker. All Rights Reserved. 5. of solid-state pharmaceuticals. A brief description of common methods will bepresented in this section.A. X-Ray DiffractionCrystalline organic solids are made up of molecules which are packed or orderedin a specic arrangement. These molecules are held together by relatively weakforces, such as hydrogen bonding and van der Waals interactions. The arrange-ment of the molecules is dened by a unit cell, which is the smallest repeatingunit of a crystal. The unit cell can be divided into planes, as shown in Fig. 3.X-ray diffraction techniques used for characterizing pharmaceutical solidsFig. 3A packing diagram of unit cells divided into planes.Copyright 2002 by Marcel Dekker. All Rights Reserved. 6. include the analysis of single crystals and powders. The electrons surrounding the atoms diffract X-rays in a manner described by the Bragg equation:n 2d sin (n 1, 2, 3, . . .) (1) where X-ray wavelengthd spacing between the diffracting planes diffraction angle A schematic of the diffraction phenomenon is given in Fig. 4. X-rays will be diffracted at an angle dened as . Knowing the diffraction angle and the X-ray wavelength, the spacing between the planes can be calculated. Conditions of the Bragg equation must be satised to achieve constructive interference of the dif- fracted X-rays and produce a beam that can be measured by the detector. If the conditions of the Bragg equation are not satised, diffracted waves interfere de- structively, with a net diffracted intensity of zero.For single-crystal diffraction, a good-quality single crystal of the sample of interest is required. From the angles and intensities of diffracted radiation, the structure of the crystal can be elucidated and the positions of the molecules in the unit cell can be determined. The result is often displayed graphically as the asymmetric unit, which is the smallest part of a crystal structure from which the complete structure can be obtained using space-group symmetry operations. Fig. 4 A schematic representation of X-ray diffraction.Copyright 2002 by Marcel Dekker. All Rights Reserved. 7. The unit cell parameters, the lengths (a, b, c) as well as the angles (, , ) ofthe unit cell are also determined from the crystal structure. There are seven classesof unit cells: triclinic, monoclinic, orthorhomic, tetragonal, hexagonal, rhombo-hedral, and cubic. For pharmaceutics, only triclinic (a b c, 90),monoclinic (a b c, 90, 90), and orthorhombic (a b c, 90) unit cells are commonly observed. The unit cells can be packed into a three-dimensional display of thecrystal lattice. The orientation of the molecules is responsible for various proper-ties of the crystalline substance. For example, hydrogen bonding networks mayprovide high stability, and spaces in the structure may allow easy access of smallmolecules to provide hydrated or solvated forms. Crystal structures provide important and useful information about solid-state pharmaceutical materials. Unfortunately, it is not always possible to growsuitable single crystals of a drug substance. In these cases, X-ray diffraction ofpowder samples can be used for comparison of samples. X-ray powder diffraction (XRPD) is the analysis of a powder sample. Thetypical output is a plot of intensity versus the diffraction angle (2). Such a plotcan be considered a ngerprint of the crystal structure, and is useful for determi-nation of crystallographic sameness of samples by pattern comparison. A crystal-line material will exhibit peaks indicative of reections from specic atomicplanes. The patterns are representative of the structure, but do not give positionalinformation about the atoms in the molecule. One peak will be exhibited for allrepeating planes with the same spacing. An amorphous sample, on the other hand,will exhibit a broad hump in the pattern called an amorphous halo, as shown inFig. 5.Fig. 5The XRPD pattern exhibited by an amorphous material.Copyright 2002 by Marcel Dekker. All Rights Reserved. 8. XRPD is dependent on a random orientation of the particles during analysis to obtain a representative powder pattern. The sample, as well as sample prepara- tion, can greatly effect the resulting pattern. Large particles or certain particle morphologies, such as needles or plates, can result in preferred orientation. Pre- ferred orientation is the tendency of crystals to pack against each other with some degree of order and it can affect relative peak intensities, but not peak positions, in XRPD patterns. If a powder is packed into an XRPD sample holder and the surface is smoothed with a microscope slide or similar device, crystals at the surface can become aligned so that a nonstatistical arrangement of crystal faces is presented to the X-ray beam. The result is that some reections are articially intensied and others are articially weakened. One way to determine if preferred orientation is causing relative peak intensity changes is