Polymorphism

Both organic and inorganic pharmaceutical compounds can crystallize into two or more solid forms that have the same chemical composition and is called as polymorphism. Polymorphs have different relative intermolecular and/or interatomic distances as well as unit cells, resulting in different physical and chemical properties such as density, solubility, dissolution rate, bioavailability, etc. When crystal structure contains solvents (or water) these are often called as psudopolymorphs with distinct physical and chemical properties. It is possible for each pseudopolymorph to have many polymorphs. In polymorphism, the crystal lattices formation can take place through two mechanisms: packing polymorphism and confor-mational polymorphism. Packing polymorphism represents formation of different crystal lattices of conformationally relatively rigid molecules that can be rearranged stably into different three-dimensional structures through different intermolecular mechanisms. When a non-conformationally rigid molecule can be folded into alternative crystal structures the polymorphism is categorized as conformational polymorphism.

Polymorphs and pseudopolymorphs can be also classified as either monotropes or enantiotropes, depending upon whether or not one form can transform reversibly to another. In a monotropic system, Form I does transform to Form II because the transition temperature cannot appear before the melting temperature (Fig. 9, monotropy). In Figure 10 (enantiotropy), Form II is stable over a temperature range below the transition temperature at which two solubility curves meet and Form I is stable above the transition temperature. At the transition temperature, reversible transformation between two forms happens. Figure 11 (enantiotropy with metastable phases) shows the kinetic effects on thermodynamic property of solubility, which shows Ostwald ripening effect. An unstable system does not necessarily transform directly into the most stable state, but into one, which most closely resembles its own, i.e., into another transient state whose formation from the original is accompanied by the smallest loss of free energy.

When the decision on whether two polymorphs are enantiotropes or monotropes need to be made, which is very useful to use the thermodynamic rules developed by Burger and Ramberger tabulated in Table 8.

The stability of polymorphs is thermodynamically related to their free energy. The more stable polymorph has the lower free energy at a given temperature. The above classification of polymorphic substances into monotropic and enantiotropic classes from the view of the lattice theory is not always appropriate. There is a need to explore how the crystal lattice structures of polymorphs are related. At a transition point with the temperature and the pressure fixed, it is possible for interconversion to happen between two polymorphs only in the case that the

FIGURE 9 Monotropic system as a function of temperature (x-axis).

FIGURE 10 Enantiotropic system as a function of temperature (x-axis).

structures of the polymorphs are related. If complete rearrangement is required by atoms or molecules during transformation, no point of contact for reversible interconversion exists. Therefore, the existence of enantiotropes or monotropes in thermodynamics and phase theory is corresponding to related or unrelated lattice structures in structural theory. Transformation between polymorphs that have completely different lattice structures exhibits the dramatic changes in properties. The difference in energy between polymorphs is not always considerable as shown with diamond/graphite. In most cases, polymorphs in this category are required to break bonds and rearrange atoms or molecules and, consequently, the polymorphs have a monotropic relation.

For the study of polymorphs that are structurally related firstly the structural relationships between the polymorphs should be established, secondly it should be explained why a particular substance is able to arrange its structural units in two closely related lattices and finally there should be a description of the manner and conditions under which rearrangement of the units from one lattice type to another can happen. For drugs that undergo degradation in the solid state, the physical form of the drug influences degradation. Selection of a polymorph that is chemically more stable is a solution in many cases. Different polymorphs also lead to different morphology, tensile strength and density of powder bed which all contribute to compression characteristics of materials. Some investigation of polymorphism and crystal habit of a drug substance as it relates to pharmaceutical processing is desirable during its preformulation evaluation, especially when the active ingredient is expected to constitute the bulk of the tablet mass.

Various techniques are available for the investigation of the solid state. These include microscopy (including hot-stage microscopy), infrared spectrophotometry, single-crystal X-ray and X-ray powder diffraction (XRPD), thermal analysis, and dilatometry.

Most organic compounds are capable of exhibiting polymorphism because of their complex flexible structure; the window of physicochemical stress that a drug is generally subjected to during manufacturing is at times not able to adduce the differentiation of a drug into its possible polymorphic forms. For example, enantiotropic state is when one polymorph can be reversibly changed into another one by varying the temperature or pressure. One way of

FIGURE 11 Enantiotropic system with metastable phases as a function of temperature (x-axis).

TABLE 8 Thermodynamic Rules for Polymorphic Transitions

Enantiotropy Monotropy

TABLE 8 Thermodynamic Rules for Polymorphic Transitions

Enantiotropy Monotropy

Transition < melting I

Transition > melting 1

I stable >transition

I always stable

II stable<transition

Transition reversible

Transition irreversible

Solubility I higher<transition

Transition I always lower

Solubility I lower>transition

Transition II -> I endothermic

Transition II -> I exothermic

A < A Mf"

A Hi > A Wf"

IR peak I before II

IR peak I after II

Density 1 < II

Density 1 > II

Abbreviation: IR, infrared.

Abbreviation: IR, infrared.

assessing whether the solid is a metastable form of the compound is to slurry the compound in a range of solvents. In this way, a solvent-mediated phase transformation may be detected using the usual techniques. The monotropic state exists when the change between the two forms is irreversible. Since all polymorphs are interchangeable, the lowest energy polymorph or the most stable polymorph is often needed to assure consistency in the physicochemical properties; this is necessary for consistency in manufacturing procedures as well as in bioavailability. The right polymorph at time is not necessarily the most stable polymorph; unstable forms like amorphous forms (that are most constrained) are often used because of their higher solubility and often a better bioavailability profile.

The manufacturing factors that may be affected by the choice of a particular polymorphic form include granulation, milling and compression, stability (particularly for semisolid forms), amount of dose delivered in metered inhalers, crystallization from different solvents at different speeds and temperature, precipitation, concentration or evaporation, crystallization from the melt, grinding and compression, lyophilization, and spray drying. In the manufacturing processing, crystallization is a major problem and it can be avoided by a careful study of polymorphic transition particularly in supercritical fluids.

Polymorphism is frequently a function of the type of salt used because the presence of counterions can cause crystallization in different forms leading to widely variable physico-chemical properties as described above under the polymorphism description. Generally, salts exhibiting polymorphism should be avoided.

An interesting example of polymorphic structure differentiation is that of HIV protease inhibitors. The HIV protease inhibitors have serious problem in their bioavailability Invirase showed only modest market performance, and it was soon superseded by drugs, such as ritonavir (Norvir®) and indinavir sulfate (Crixivan®) that had better bioavailability. Three years after initial approval, saquinavir was reintroduced in a formulation with sixfold higher oral bioavailability relative to the original product. Ritonavir was originally launched as a semisolid dosage form, in which the waxy matrix contained dispersed drug in order to achieve acceptable oral bioavailability. Two years after its introduction, ritonavir exhibited latent crystal polymorphism which caused the semisolid capsule formulation of Norvir to be removed from the market.

Each polymorph has a certain thermodynamic energy associated with it as a result of strains in the bonds of the lattice structure, and therefore one polymorph may be more stable than the others. At any given temperature and pressure only one crystal form of a drug will be stable, and other forms will convert to this form. When the conversion is relatively slow, the polymorph is said to be metastable. The various polymorphic forms are chemically indistinguishable. However, they differ in physical properties, such as density, melting point, solubility, and dissolution rates. For example, riboflavin exists in several polymorphic forms with a 20-fold difference in their aqueous solubility. Amorphous forms in which no internal crystal structure exists have the highest solubilities, giving the order of dissolution rates for the crystal forms can be arranged as amorphous >metastable>stable forms.

TABLE 9 Effect of Polymorphism on Dosage Form Characteristics

Example

Explanation

Novobiocin Sulfathiazole Lente insulin Theobroma oil Penicillin G

Chloramphenicol stearate Aspirin, barbital, estrone, sulfonamides, chloramphenicol, chlordiazepoxide, adiphenine, erythromycin, methotrexate, cholesteryl palmitate

Increased BA from amorphous form, suspension stabilized by methyl cellulose Increased dissolution from amorphous form conversion stabilized by PEG 400 Amorphous form for quick absorption, crystalline form giving sustained delivery High melting point form for room temperature stability

Amorphous form less chemically stable Amorphous form active Altered bioavailability

Abbreviations: BA, bioavailability; PEG, polyethylene glycol.

It has been suggested that almost 40% of all organic compounds can exist in various polymorphic forms; sometimes in as many as five different forms, as in the case of cortisone acetate; almost 50% of all barbiturates and 70% of steroids exhibit polymorphism.

This premise, however, may not be applicable to all drugs, especially those which are absorbed by an active process, e.g., various vitamins. Table 9 lists effects of polymorphism on drug and dosage form characteristics.

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