Physical Pharmacy Physical Chemical Principles

Physical pharmacy is a term that came into common use in the pharmacy community in the mid-twentieth century, and the field has grown and evolved over the years. Essentially, physical pharmacy is a collection of basic chemistry concepts that are firmly rooted in thermodynamics and chemical kinetics. Scientists in the mid-twentieth century pioneered research in the areas of physical-chemical properties of drugs and their influence on biological performance (Reinstein and Higuchi, 1958; Higuchi, 1958, 1976; Higuchi et al., 1956, 1958, 1963; Kostenbauder and Higuchi, 1957; Shefter and Higuchi, 1963; Agharkar et al., 1976; Shek et al., 1976). Key aspects of physical-chemical properties discussed in greater detail in Chap. 2, briefly include the following.

1.1.2.1 Solubility

Solubility is a thermodynamic parameter that defines the amount of material (in this case a drug) that can dissolve in a given solvent at equilibrium. Solubility is one of the most critical and commonly studied physical-chemical attributes of drug candidates. The amount of drug in solution as a function of time prior to reaching equilibrium is often referred to as the "kinetic solubility," which can be exploited in pharmaceutical applications to manipulate drug delivery. A compound's solubility impacts its usefulness as a medicinal agent and also influences how a compound is formulated, administered, and absorbed. A thorough review of the scientific fundamentals of solubility theory has been presented previously (Flynn, 1984).

1.1.2.2 Hydrophilicity/Lipophilicity

The partition or distribution coefficient of a drug candidate (log P or log D) is a relative measure of a compound's tendency to partition between hydrophilic and lipophilic solvents and thus indicates the hydrophilic/lipophilic nature of the material. The relative lipophilicity is important with respect to biopharmaceutics since it affects partitioning into biological membranes and therefore influences permeability through membranes as well as binding and distribution into tissues in vivo (Ishii et al., 1995; Lipka et al., 1996; Merino et al., 1995).

1.1.2.3 Salt Forms and Polymorphs

Drug substances can often exist in multiple solid-state forms, including salts (for ionizable compounds only), solvates, hydrates, polymorphs, co-crystals or amorphous materials. The solid form of the compound affects the solid-state properties including solubility, dissolution rate, stability, and hygroscopicity, and can also impact drug product manufacturability and clinical performance (Singhal and Curatolo, 2004). There are numerous examples in the literature of the impact of pH and salt form on solubility, and how this phenomenon can be utilized to manipulate the solubility behavior of a drug compound (Li et al., 2005; Agharkar et al.,

1976; Morris, 1994). For example, salts can be chosen to impart greater solubility to improve dissolution rate of an active pharmaceutical ingredient (API). Polymorphs and solvated forms of drug candidates can also affect not only the stability and manufacturability of a drug substance but also potentially impact biopharma-ceutical performance due to their differing solubilities (Raw and Yu, 2004).

1.1.2.4 Stability

The chemical stability of a drug is important in order to avoid generation of undesirable impurities, which could have pharmacologic activity and/or toxicologic implications, in the drug substance or drug product. Chemical stability of the API in a dosage form influences shelf-life and storage conditions of drug products to minimize generation of undesirable impurities. The pH-stability profile is also important from a physiological perspective considering the range of pH values that a pharmaceutical material may encounter in vivo, particularly in the GI tract. Sufficient stability is required for the compound as well during the course of administration. Physical stability refers to changes in the drug substance solidstate form including polymorphic transitions, solvation/desolvation, or salt dispro-portionation. As mentioned previously, changes in drug substance form can lead to changes in physical properties such as solubility and dissolution rate. At the product (dosage form) level, physical stability refers broadly to mechanical property integrity (hardness, friability, swelling) and potential impact of changes on product performance.

1.1.2.5 Particle and Powder Properties

Bulk properties of a pharmaceutical powder include particle size, density, flow, wettability, and surface area. Some are important from the perspective of a manufacturing process (e.g., density and flow) while others could potentially impact drug product dissolution rate (particle size, wettability, and surface area) without changing equilibrium solubility.

1.1.2.6 Ionization and pKa

The ionization constant is a fundamental property of the chemical compound that influences all of the physical-chemical properties discussed above. The presence of an ionizable group (within the physiologically relevant pH range) leads to pH-solubility effects, which can be used to manipulate the physical properties and biological behavior of a drug. For an ionizable compound, the aqueous solubility of the ionized species is typically higher than the unionized due to the greater polarity afforded by the presence of the ionized functional group. The ionizable functional group and the magnitude of the pKa determine whether a compound is ionized across the physiological pH range, or if conversion between ionized/nonionized species occurs in the GI tract, and if so, which region. The pKa also affects the available choices of counterions for potential salt forms that are suitable from a physical perspective.

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