Hydrates pseudopolymorphs

Undoubtedly, many of the above and other examples have been caused by unintentional seeding. Reference has already been made in section 5.1.2 to the role atmospheric dust can play as a nucleating agent, noting that even foreign bodies in the dust can also act as nucleation promoters. Once a certain crystalline form has been prepared in a laboratory or plant, the working atmosphere inevitably becomes contaminated with seeds of the particular material. If later a thermodynamically more stable polymorph or hydrate (pseudopolymorph) appears, then seeds of this too will enter the atmosphere and play a dominant role. However, it is the speed with which another laboratory or plant, often some large distance apart, sometimes even in another country, also become... 

The phenomenon of pseudopolymorphism is also observed, i.e., compounds can crystallize with one or more molecules of solvent in the crystal lattice. Conversion from solvated to nonsolvated, or hydrate to anhydrous, and vice versa, can lead to changes in solid-state properties. For example, a moisture-mediated phase transformation of carbamazepine to the dihydrate has been reported to be responsible for whisker growth on the surface of tablets. The effect can be retarded by the inclusion of Polyoxamer 184 in the tablet formulation [61]. 

The utilization of IR spectroscopy is very important in the characterization of pseudopolymorphic systems, especially hydrates. It has been used to study the pseudopolymorphic systems SQ-33600 [36], mefloquine hydrochloride [37], ranitidine HC1 [38], carbovir [39], and paroxetine hydrochloride [40]. In the case of SQ-33600 [36], humidity-dependent changes in the crystal properties of the disodium salt of this new HMG-CoA reductase inhibitor were characterized by a combination of physical analytical techniques. Three crystalline solid hydrates were identified, each having a definite stability over a range of humidity. Diffuse reflectance IR spectra were acquired on SQ-33600 material exposed to different relative humidity (RH) conditions. A sharp absorption band at 3640 cm-1 was indicative of the OH stretching mode associated with either strongly bound or crystalline water (Fig. 5A). The sharpness of the band is evidence of a bound species even at the lowest levels of moisture content. The bound nature of this water contained in low-moisture samples was confirmed by variable-temperature (VT) diffuse reflectance studies. As shown in Fig. 5B, the 3640 cm-1 peak progressively decreased in intensity upon thermal... 

A.M. Amado, M.M. Nolasco and P.J.A. Ribeiro-Claro, Probing pseudopolymorphic transitions in pharmaceutical solids using Raman spectroscopy Hydration and dehydration of theophylline, J. Pharm. Sci., 96, 1366-1379 (2007). 

The importance of polymorphism in pharmaceuticals cannot be overemphasized. Some crystal structures contain molecules of water or solvents, known as hydrates or solvates, respectively, and they are also called as pseudopolymorphs. Identifying all relevant polymorphs and solvates at an early stage of development for new chemical entities has become a well-accepted concept in pharmaceutical industry. For poorly soluble compounds, understanding their polymorphic behavior is even more important since solubility, crystal shape, dissolution rate, and bioavailability may vary with the polymorphic form. Conversion of a drug substance to a more thermodynamically stable form in the formulation can signiLcantly increase the development cost or even result in product failure. 

A typical example of the characterization of a polymorphic system by FT Raman spectroscopy has been given by Gu and Jiang (1995) while an application of the technique with near infrared excitation to the polymorphic cimetidine system has been described by Tudor et al. (1991). The FT Raman technique has been compared to infrared diffuse reflection spectroscopy in the study of the polymorphs of spironolactone (Neville et al. 1992), and the pseudopolymorphic transition of caffeine hydrate (i.e. loss of solvent) has been monitored using the technique (de Matas et al. 1996). 

Hydrates normally form crystal structures (pseudopolymorphs) that differ from the anhydrous form. Different powder XRD patterns of ampicillin in the anhydrous and trihydrate forms are shown in Fig. 16. Although moisture contents often present values that are close to being stoichiometric, X-ray confirmation of the differing crystal structure should be a requisite for designation as a hydrate. 

Solid Form Selection A drug can exist in multiple forms in the solid state. If the two forms have the same molecular structure but different crystal packing, then they are polymorphs. Pseudopolymorphs (or solvatomorphs) differ in the level of hydration/solvation between forms. Polymorphs and pseudopolymorphs in principle will have a different solubility, melting point, dissolution rate, etc. While less thermodynamically stable, polymorphs have higher solubilities they also have the potential to convert to the more thermodynamically stable form. This form conversion can lead to reduced solubility for the formulated product. One example is ritonavir, a protease inhibitor compound used to treat acquired immune deficiency syndrome (AIDS). Marketed by Abbott Labs as Norvir, this compound began production in a semisolid form and an oral liquid form. In July 1998, dissolution tests of several new batches of the product failed. The problem was traced to the appearance of a previously unknown polymorph (Form II) of the compound. This form is thermodynamically more stable than Form I and therefore is less soluble. In this case, the solubility is at least a factor of 2 below that of Form I.12 The discovery of this new polymorph ultimately led to a temporary withdrawal of the solid form of Norvir from the market and a search for a new formulation. 

Polymorphism, as applied to the sohd state, can be defined as the ability of the same chemical substance to exist in different crystalline structures (Findlay et al. 1951) (regular, repeating arrangement of atoms or molecules in the solid state). The different structures are generally referred to as polymorphs, polymorphic modifications, crystal forms, or forms (Verma and Krishna 1966). Strict adherence to this definition of polymorphism excludes solvates and hydrates (specific water solvate) as polymorphs because they correspond to different chemical substances. Solvates and hydrates are sometimes referred to as pseudopolymorphs. Molecule A is a different chemical substance than molecule A coordinated with a solvent. 

Polymorphs are crystalline solids that have the same chemical composition, yet adopt different molecular arrangements in the crystal lattice (Grant, 1999 Byrn et al., 1999 Vippagunta et al., 2001 Bernstein, 2002). Crystalline solids may also incorporate solvent into the lattice during crystallization to form a solvate, or a hydrate in the case of water, an occurrence that is commonly referred to as pseudopolymorphism (Bym et al., 1999 Nangia and Desiraju, 1999). Adequate control over the crystallization of solid forms is of utmost importance, as each form can exhibit different pharmaceutically relevant properties including solubility, dissolution rate, bioavailability, physical and chemical stability, and mechanical properties (Grant, 1999 Bernstein, 2002). 

A large proportion of drug substances, whether neutral molecules, free adds, free bases or salts, are capable of exhibiting polymorphism or pseudopolymorphism (hydrate or solvate formation). It has been reported that 70% of barbiturates, 60% of sulfonamides and 23% of steroids exhibit polymorphism." Polymorphism often influences a range of physicochemical properties such as solubility, dissolution rate, stability and powder properties as well as bioavailability. Usually, it is possible to determine the most stable polymorph and discover recrystallization solvents that uniquely produce this form and improve the physicochemical and physicome-chanical properties and chemical stability of the drug. 

Polymorphism The occurrence of different crystalline forms of the same drug substance. This may include solvation or hydration products (also known as pseudopolymorphs) and amorphous forms. 

Pseudopolymorphs are not strictly polymorphs because they differ from each other in the solid crystalline phase, such as through the incorporation of solvents (solvates) or water (hydrates). Pseudopolymorphsmay also be suitable for development and should be identified and evaluated during solid form screening activities. 

Hydrates. Generally, hydrates are considered appropriate pseudopolymorphs for development. Many drugs are marketed as hydrates, presumably because they are either the most stable form at "typical" relative humidities or because they offer other drug delivery advantages. Hydrates often, though not always, are less soluble in water than the corresponding anhydrous form. If the hydrate is less soluble, it often crystallizes when the anhydrous form is suspended in water and allowed to equilibrate. 

When a material can crystallize into a different polymorph, the chemical nature of the species remains identical, however, the physical properties of the material can be different. For example, properties such as density, heat capacity, melting point, thermal conductivity, and optical activity can vary from one polymorph to another. Table 2.3 lists common materials that exhibit polymorphism. Looking at Table 2.3 we can see that density varies significantly for the same materials when the crystal structure has changed. In addition, the change in the crystal structure often means a change in the external shape of the crystal, which is often an important parameter in industrial crystallization that has to be controlled. Many substances crystallize into structure in which the solvent is present as part of the crystal lattice. These crystals are known as solvates (or hydrates when the solvent is water). A substance can have multiple solvates with different crystal structures as well as a solvent free crystal form with a unique crystal structure. The solvates are often referred to as pseudopolymorphs. They are not true polymorphs because of the addition of the solvent molecule(s) to the crystal lattice. Conformational polymorphism refers to the situation where the molecular conformation of the molecules of a given substance are different in each polymorph. 

Accelerated stability studies are potentially problematic for at least three reasons. Stress testing conditions may exceed the temperature of a polymorphic phase transition or dehydration. The use of accelerated conditions may make a relaxation of a metastable phase more rapid due to the increased molecular mobility. Finally, the relative humidity of the station may be in the range sufficient to cause a pseudopolymorphic transition due to dehydration or hydration. It is sobering... 

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