Polymorphism and Its Clinical Implications

Polymorphism and its Clinical Implications

• Polymorphism is a phenomenon where a compound can exist in multiple crystal structures, each with unique physical and chemical properties.
• Different crystal habits (external shapes) result from different crystal structures.
• Similar internal structure and XRD patterns can exist but lead to different properties between compounds.
• Compounds crystallize as different polymorphs depending on crystallization conditions.

Overview

• Polymorphism is defined as the ability of a substance to exist in multiple crystalline forms.
• The pharmaceutical and clinical implications of polymorphism are substantial, impacting drug stability, dissolution rate, bioavailability, and potential for adverse effects.
• Polymorphic forms have similar chemical composition but different crystal structures leading to differences in their physical and chemical properties.

Polymorphism Point to Understand

• Polymorphism means a substance existing in multiple crystalline forms.
• Polymorphs differ in physical traits but have the same chemical structure.
• Polymorphism is related to crystallization conditions.

Compounds

• Compounds crystallize out of differing solution habits depending on the conditions of crystallization.
• Crystal habits have comparable internal structures and XRD patterns.
• Compounds crystallize as different polymorphs influencing properties.

Analytical Techniques for Solid State Characterization

• Powder X-ray Diffractometry (PXRD) is a crucial technique for identifying crystalline phases.
• Single crystal XRD provides detailed structural information.
• XRD measures average atomic layer spacing.
• XRD is used to determine crystal structure.
• XRD establishes phase compositions and material properties.
• XRD differentiates polymorphs by their distinct diffraction patterns.

Why XRD?

• Measures average interatomic distances
• Determines crystal orientation
• Identifies unknown materials
• Establishes phase composition & material properties
• Differentiates polymorphs.

95% of all solid materials are crystalline

• When X-rays interact with a crystalline substance, diffraction patterns are created.
• The diffraction patterns reveal the crystalline structure.

X-ray Diffraction (XRD)

• Sir Bragg related X-ray beams at particular angles to crystal faces.
• Bragg's Law (nλ = 2d sin θ) relates wavelength, angle, and spacing between atomic layers.

Variables in Bragg's Law

• d = distance between atomic layers
• λ = wavelength of incident X-ray beam
• θ = angle of incidence (Bragg's angle)
• n = integer

Pharmaceutical Implications of Polymorphism

• Problems in tableting and injections can stem from differences in crystal habits, influencing processing.
• Polymorphs have distinct properties, impacting stability and biopharmaceutical behavior.
• The most stable polymorphic form has the lowest free energy.

Differential Scanning Calorimetry (DSC)

• DSC measures the heat flow during phase transitions, identifying crystalline forms and interactions with excipients.
• "Black box" technique, providing no information about the transition's essential nature.

Thermogravimetric Analysis (TGA)

• TGA measures weight changes during heating determining the stoichiometry of solvates/hydrates.
• Interferences occur due to water-containing excipients.

Polymorphs and different properties

• Polymorphs display different physical and chemical characteristics (e.g., melting point, solubility).
• Different crystal habits (external appearances) are observed in various polymorphs.

Spironolactone Polymorphic Forms

• Polymorphic forms of spironolactone display different crystal structures yielding different properties, such as melting points.
• The production process, crystal form, melting point and axes (nm) for both Form 1 and Form 2 are compared.

Paracetamol Polymorphic Forms

• Two crystalline forms of paracetamol (PCM) exist—Form I and Form II—differing in properties and physical behavior.
• Form I is plate-like, more stable and less suitable for direct compression, while Form II is prism-like and less stable, readily undergoing plastic deformation under compaction.

Phenobarbitone and Barbiturates

• Phenobarbitone exists in multiple crystalline forms.
• Barbiturates (e.g. various forms of a given compound) exhibit polymorphic characteristics.

Polymorphic Drugs and Their Characteristics

• Various drugs exhibit polymorphic and pseudopolymorphic forms influencing properties such as solubility and melting points.
• Drugs exhibit a wide variety of polymorphic and pseudopolymorphic forms.

Crystal Solvate and Pseudopolymorphic Solvates

• Crystalline solvates contain solvent molecules within their crystal structure, influencing properties.
• Pseudo-polymorphic solvates merely occupy crystal voids.

Polymorphic Transformations

• Transformations between polymorphic forms can cause issues in drug formulations; for example, the formation of caked powders.

Analytical Issues and Consequences

• Infrared spectroscopy (FTIR), in particular, demonstrates variation in spectra for different polymorphs.
• Polymorphic considerations in drug formulations are essential.
• Differences in polymorphs are significant concerning bioavailability.
• Polymorphic differences can influence drug stability, and dissolution rates, hence affecting the treatment efficacy.

Clinical Examples and Impact on Treatment

• Gout arises from uric acid crystal accumulation causing joint inflammation and pain.
• Kidney stones are crystalline formations comprising minerals, oxalates, and uric acid contributing to urinary tract discomfort.
• Amyloidosis involves abnormal proteins accumulating in organs, impacting organ functions.

This quiz explores the concept of polymorphism, focusing on its significance in pharmaceuticals and clinical settings. Understand how different crystalline forms of compounds affect drug properties such as stability, dissolution rate, and bioavailability. Dive into the implications of polymorphism on drug development and patient safety.