Bioavailability crystal polymorphisms

A dramatic example of the impact of crystal polymorphism on a drug formulation is that of ritonavir (Norvir ), used for the treatment of HIV patients. The problem arose in May of 1998, approximately two years after the launch of the drug, when researchers at the Abbott Laboratories became aware that after 240 production batches it was no longer possible to obtain ritonavir in the crystal form (Form I) approved by the FDA and required for the formulation of Norvir because of the sudden and unexpected appearance of a more stable and much less soluble crystal form (Form II, Fig. 3.3.17). The loss of control over the production process forced Abbott to withdraw the drug from the market for approximately one year until they learned how to replace the solid formulation with a gel capsule suspension with greater problems of stability and bioavailability. Subsequent investigations have led to the discovery of four other crystalline forms of ritonavir [33]. 

Selection of the most suitable chemical form of the active principle for a tablet, while not strictly within our terms of reference here, must be considered. For example, some chloramphenicol esters produce little clinical response [13], There is also a significant difference in the bioavailability of anhydrous and hydrated forms of ampicillin [14], Furthermore, different polymorphic forms, and even crystal habits, may have a pronounced influence on the bioavailability of some drugs due to the different dissolution rates they exhibit. Such changes can also give rise to manufacturing problems. Polymorphism is, of course, not restricted to active ingredients, as shown, for example, in an evaluation of the tableting characteristics of five forms or sorbitol [15]. 

The physical characteristics should be considered (in combination as appropriate) in relation to the proposed dosage form and route of administration. Factors to be considered extend to solubility characteristics, crystal form and properties, moisture or solvent content, particle size and size distribution (which may affect bioavailability, content uniformity, suspension properties, stability, and preclinical or clinical acceptability), polymorphism, etc. 

The results of the polymorph screening step in combination with bioavailability studies, provide the information required by the clinical research team to nominate the desired crystal form of the API for long term manufacture and formulation. This form will usually be the most stable polymorph, where a number of forms have been identified, or a salt form if bioavailability is low or when there are formulation concerns regarding polymorph stability. In some cases it may be necessary to select an amorphous form or metastable polymorph because of crystallization difficulties, time constraints or bioavailability requirement. The nomination of a hydrate or solvate is generally avoided because of their relative instability and compositional variability such constraints are less of a concern for the earlier synthetic intermediates. 

Polymorphs and solvated crystals is generally observed in pharmacentical indnstry [1], The bioavailability, stability, solnbility, and morphology of the pharmacentical products are very influenced by polymorphs [2-7], therefore the control of the polymorphic crystallization is very important. The crystallization process of polymorphs and solvated crystals is composed of competitive nucleation, growth, and transformation from a meta-stable form to a stable form [4], Furthermore, the crystallization behavior is influenced by various controlling factors such as temperature, supersaturation, additives and solvents [8], In order to perform the selective crystallization of the polymorphs, the mechanism of each elementary step in the crystallization process and the key controlling factor needs to be elucidated [8], On the other hand, we reported for L-Glutamic acid and L-Histidine system previously [4] that the nucleation and transformation behaviors of polymorphs depend on the molecular stractures. If the relationship between molecular stmcture and polymorphic crystallization behavior is known, the prediction of the polymorphism may become to be possible for the related compound. However, detail in such relationship is not clearly understood. 

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. 

Besides regulatory importance, salts, polymorphs, and hydrates/solvates have clear novelty and patentability considering their different chemical compositions or distinguishable solid state ( fon Raumer et al., 2006). Those new forms can affect not only their processibilities, such as crystallization,Lltration, and compression, but also their biological properties, such as solubility and bioavailability. Besides, the manufacturing processes for those forms are often innovative, and thus patentable. 

The majority of all APIs manufactured demonstrate structural polymorphism. In order to formulate a drug product that is physically and chemically stable, the formulation team must identify the most thermodynamically stable polymorph of the API. By identifying the proper polymorph, the patient s need for a drug product with reproducible bioavailability during the course of typical and atypical shelf-life conditions will be met. This section will review the use of spectroscopic techniques for identifying polymorphism of APIs during API crystallization and formulation. For a more comprehensive discussion of polymorphism the reader is directed to a work by Singhal85 and references cited therein. 

The crystal structure of the cocrystal formed by celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide) with nicotinamide has been solved from powder X-ray diffraction data [54], The dissolution and solubility of the cocrystal product were found to depend on the medium involved, and a number of the observed phenomena were shown to originate from differences in conversion of the cocrystal celecoxib polymorphic forms I and III. However, through the judicious use of choice excipients, a formulation was developed that took advantage of the crystalline conversion to be up to fourfold more bioavailable than the celecoxib Form-Ill marketed product. 

While establishing molecular networks for cocrystal design and determining crystal structures is very important, the value of cocrystals of pharmaceutical components lies in the ability to tailor the functionality of materials. In contrast to polymorphs that have the same chemical composition, cocrystals do not. As such, one would expect that with cocrystals one could introduce greater changes in material properties than with polymorphs. Properties that relate to pharmaceutical performance and that can be controlled by cocrystal formation include melting point, solubility, dissolution, chemical stability, hygroscopicity, mechanical properties, and bioavailability. The cocrystals for which pharmaceutical properties have been studied are few and some of these are presented below. Clearly further research in this area is needed. 

Polymorphism is the ability of a chemical species to crystallize in more than one distinct crystal habit. The pharmaceutical applications of polymorphism have been reviewed by several authors. The differences in dissolution rate and solubility that polymorphs can produce may have a dramatic impact on bioavailability when dissolution is the rate-limiting step in the absorption process. 

Subsequently, workers in pharmaceutically related fields realized that the solid-state property differences derived from the existence of alternate crystal forms could translate into measurable differences in properties of pharmaceutical importance. For instance, it was found that various polymorphs could exhibit different solubilities and dissolution rates, and these differences sometimes led to the existence of nonequivalent bioavailabilities for the different forms. Since then, it has become recognized that an evaluation of the possible polymorphism available to a drug substance must be thoroughly investigated early during the stages of development. In various compilations, it has been reported that polymorphic species are known for most drug substances and that one should be surprised to encounter a compound for which only one structural type can be formed. 

Internal structure (unit cell) can be different in crystals that are chemically identical. This is called polymorphism. Polymorphs can vary substantially in physical and chemical properties such as bioavailability and solubility. They can be identified by analytical techniques such as X-ray diffraction, infrared, Raman spectro, and microscopic techniques. For the same internal structure, very small amounts of foreign substances will often completely change the crystal habit. The selective adsorption of dyes by different faces of a crystal or the change from an alkaline to an acidic environment will often produce pronounced changes in the crystal habit. The presence of other soluble anions and cations often has a similar influence. In the crystallization of ammonium sulfate, the reduction in soluble iron to below 50 ppm of ferric ion is sufficient to cause significant change in the habit of an ammonium sulfate costal from a long, narrow form to a relatively chunky and compact form. Additional information is available in the patent literature and Table 18-4 lists some of the better-known additives and their influences. 

In the pharmaceutical industry, SSNMR is commonly used to study polymorphism, hydrogen bonding, crystal packing, and solid-solid interactions. Shelf life or activity decay is often determined by the bioavailability of different polymorphs. Fig. 12 shows very different CP/MAS spectra from two polymorphs of an analgesic, flufenamic acid. It is also used for the study of inclusion complexes, drug-excipient interactions, or the effect of moisture on drug substances or formulations. 

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). 

Many solid compounds are known to exist in different crystalline modifications such as amorphous, crystalline or glassy states affecting solubility, dissolution rate, stability and bioavailability. In order to improve the pharmaceutical potential, therefore, it is important to control the crystallization, the polymorphic transition, and whisker generation of solid drugs. ... 

---