Different lattice energies associated with physical forms such as polymorphs, solvates, and amorphous give rise to measurable differences in physicochemical properties, including solubility and stability (Grant and Highuchi, 1990). Thus understanding solid state properties is important in designing robust formulations with optimal biopharmaceutical properties.
Polymorphism is defined as a solid crystalline phase of a given compound resulting from the possibility of at least two different arrangements of that compound in the solid state (Haleblain and McCrone, 1969). In addition to polymorphs, compound may also exist as solvates and hydrates (sometimes also called pseudo-polymorphs), where solvent or water is included in the crystal lattice, and amorphous forms, where no long-range order exists.
In general, polymorphs and pseudo-polymorphs of a given drug have different solubility, crystal shape, dissolution rate, and thus possibly absorption rate. Conversion of a drug substance to a more thermodynamically stable form in the formulation can sometimes significantly increase the development cost or even result in product failure. Therefore, it is generally accepted that the thermodynamically most stable form is identified and chosen for development.
An early study by Aguiar et al. (1967) on chloramphenicol palmitate suspension is a classic example showing the effect of polymorphs on bioavailability. Since then, there are only limited number of studies reported. This may partially be due to the fact that most of metastable forms are not chosen for development, and therefore are not tested in human. Recently, Pudipeddi and Serajuddin (2005) reviewed a large number of literature reports on solubility or dissolution of polymorphs and found that the ratio of polymorph solubility is typically less than 2, although occasionally higher ratios can be observed. Higher and more spread out ratios were found when anhydrates were compared to hydrates. For a compound that has low bioavailability due to solubility or dissolution rate-limited absorption, a drop of two times in solubility may directly result in a two time reduction in bioavailability. On the other hand, different crystal forms of highly soluble drugs should not affect bioavailability since solubility or dissolution rate is not likely to be the limiting factor for absorption for these compounds.
Identifying the thermodynamically most stable form and the potential for the hydrate formation is probably the most important part of studying polymorphism. There are many ways to screen for polymorphs, solvates, and hydrate. Crystallization from solution and recrystallization from neat drug substance are two most commonly applied methods (Guillory, 1999). Several high throughput methods with automated or semi-automated sample handling and characterization for crystal screening have been reported. While these new methodologies provide extra capacities for solid form discovery, it still requires detailed characterization and analysis to understand the interrelationship of various forms. One of the methods that are very useful in identifying the lowest energy form is the slurry experiment. Typically, an aqueous based solvent and a water-free solvent are chosen for these studies. After all the forms are suspended in these two solvents for a certain period of time, a conversion of various forms to the lowest energy form or the hydrate will typically occur.
Theoretically, the amorphous form of a material has the highest free energy, thus should have the biggest impact on solubility and bioavailability. A review of the data in the literature indicates that improvements in solubility resulting from the use of amorphous material can range from less than two-fold to greater than 100-fold (Hancock and Zografi, 1997). Elamin et al. (1994) even showed that low levels of amorphous character induced in griseofulvin by milling, which were undetectable by DSC, can readily result in solubility differences of two-fold or more. Thus, it is important to understand the impact of pharmaceutical processing such as wet granulation and roller compaction on the crystallinity of drug substance in order to have a robust process with adequate control for product quality.
Since amorphous material typically is not stable in any solvents, measuring the true equilibrium solubility of amorphous material is very difficult. Thus, the solubility advantage determined experimentally is typically less than that predicted from simple thermodynamic considerations. Hancock and Parks (2000) suggested that the true solubility advantage for amorphous material could be as high as over 1,000-fold.
To take advantage of the amorphous solubility, the amorphous material needs to be physically and chemically stable in a given dosage form. To overcome the challenge, the amorphous material is typically formulated in a solid dispersion formulation. Polymers are typically employed to increase the glass transition temperature (Tg). It is typically believed that a 50°C difference between the Tg of a solid dispersion and storage temperature is required in order to minimize the mobility and reduce the risk for crystallization.
Recently, Vasanthavada et al. (2004, 2005) showed that when a drug in its amorphous stage is miscible with a polymer in a solid dispersion, it can be physically stable even under accelerated stability condition (high temperature and high humidity). They developed a method to determine the "extent of molecular misci-bility," referred to as "solid solubility," and demonstrated that hydrogen bonding is the main contributor to the solid solubility for the indoprofen and poly vinyl pyrrolidone (PVP) system. The method developed should be an excellent tool useful for identifying carriers that can form physically most stable solid dispersions.
Particle size is an important physical property impacting oral absorption because it is directly related to surface area available for dissolution. For compounds whose bioavailability is limited by the dissolution rate, it is obvious that particle size reduction should enhance absorption.
Further increase in absorption can be realized by reducing particles to submicron size (Rabinow, 2004). However, when the particles are reduced to submicron size, they tend to agglomerate to reduce the free energy of the system. This tendency is resisted by the addition of surface-active agents, which reduce the interfacial tension and therefore also the free energy of the system.
A variety of techniques with different operating principles and features are available for measuring particle size distribution. Sieving or screening and microscopy are commonly used for large particles typically used for solid dosage form development. Laser light diffraction can be used for particle size ranging from 0.02 up to 2,000 |im. However, the limitation of this method is that it is not measuring a single particle rather it is measuring an ensemble of particles. For particles at nanomicron ranges, some special techniques such as field emission low-voltage scanning electron microscopy and photon-correlation spectroscopy have been used.
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