Physical Pharmacy Lecture 2: Polymorphism of Solids

Polymorphism

• Polymorphism is a property of crystalline solids, where molecules arrange or orient themselves in two or more different ways.
• Polymorphs have different physical properties, such as melting point, solubility, and X-ray diffraction.
• Formation of polymorphs depends on the conditions of crystallization, solvent used, rate of crystallization, impurities, supersaturation, and temperature.

Types of Polymorphic Transitions

• Monotropic transition: a transition that takes place in one direction only, for example, from a metastable to a stable form.
• Enantiotropic transition: a reversible change of the polymorphic forms from one to another.

Properties of Polymorphs

• Stable polymorph represents the lowest energy state and has the highest melting point and the least aqueous solubility.
• Metastable form represents the higher energy state and has a lower melting point and high aqueous solubility.
• Metastable form converts to the stable form due to their higher energy state.

Cocoa Butter

• Cocoa butter has 4 polymorphic forms: meta-stable gamma (18°C), alpha form (22°C), beta prime form (28°C), and stable beta form (34.5°C).
• The stable beta form is best suited for use as a suppository base.

Pseudo-Polymorphism

• Pseudo-polymorphism is caused by changes in the crystallization process, which results in the inclusion of solvent molecules in the crystal, producing solvates or hydrates.
• Solvates or hydrates differ in properties from the non-solvated sample, just like different polymorphic forms.
• Different solvates of the same drug can produce different blood concentrations from the administered solid oral dosage form.

Solvates and Hydrates

• Solvates: crystalline structures in which solvent molecules are incorporated into the crystal lattice, exhibiting different physical properties compared to the anhydrous form.
• Hydrates: crystalline forms of a substance in which water molecules are incorporated into the crystal lattice, affecting properties such as solubility and stability.

X-Ray Diffraction

• X-ray diffraction method is used to differentiate between solvates and true polymorphs by changing the temperature.
• Amorphous compounds have no definite peak in X-ray spectra.

Thermal Analysis

• Thermal analysis methods are used to characterize the physical and chemical changes of materials upon heating or cooling.
• Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) are commonly used methods.
• Thermal analysis is important for the determination of purity, polymorphism, moisture content, amorphous content, and stability.

TGA (Thermogravimetric Analysis)

• TGA is used to measure residual solvents and moisture, and can also be used to determine solubility of pharmaceutical materials in solvents.
• Analysis of pharmaceutical materials is a large area of application for thermal analysis.
• Three types of thermogravimetry are used.