Polymorph Screening to support Pharmaceutical Development

Polymorphism

Many pharmaceutical compounds are polymorphic, i.e. they exhibit more than one crystalline form. Different polymorphs of an active pharmaceutical ingredient have different physical and chemical properties. These variations give rise to differences in solubility, stability, and bioavailability that can impact the safety and efficacy of new therapeutic agents. It is therefore important to evaluate each drug candidate for polymorphism (polymorph screening). For drug systems exhibiting polymorphism, each form should be characterized in order to establish which is the most stable. After characterization of the polymorphic system, a robust production process must be developed to reliably produce the desired polymorph (polymorph process development).

Polymorph Screening

Ricerca uses robotic equipment to perform solvent recrystallization to evaluate APIs for polymorphism. The recrystallized solids are analyzed by powder x-ray diffraction to determine if different crystalline forms exist. Any additional polymorphs can be characterized and produced in amounts sufficient for additional characterization studies.

Pseudopolymorphism (hydrates & solvates)

The chemical and physical properties of pharmaceutical solids also depend on moisture content. Many compounds undergo changes in hydration state with corresponding changes in ambient humidity. Because water vapor is present during virtually all facets of pharmaceutical development, a fundamental understanding of the relationship between water sorption and relative humidity is necessary. Water sorption isotherms are generated by monitoring water content as the relative humidity is manipulated. X-ray diffraction and thermal analysis are used to determine if different states of hydration exist. Compounds exhibiting multiple hydrated states are often referred to as pseudopolymorphs.

Polymorph Characterization

Ricerca characterizes polymorphic active ingredients by determining the chemical and physical properties of each form. The thermodynamic hierarchy of the polymorphs is evaluated to provide insight into the stability relationships among the different polymorphs. The spectral and powder characteristics of each form are also determined. Solubility, dissolution rate, bioavailability, and pharmacokinetics of each polymorph can also be characterized. An example of a stability hierarchy for a compound having three polymorphs is shown below. Under ambient conditions, generally only one polymorph is stable. All other solid state forms are metastable relative to the stable form. Characterization of polymorphs at Ricerca includes determining the energy (or stability) relationship among different polymorphs of a given active ingredient. The polymorph with the lowest energy at any temperature is the most stable form.

Polymorph Process Development

Ricerca has the process development and engineering capabilities to develop a robust process for the production of the desired form of a given drug.

Analytical Techniques Used in Polymorph Investigations

X-ray Diffraction Analysis
Thermal Analysis
   - Differential Scanning Calorimetry (DSC)
   - Thermogravimetric Analysis (TGA)
Particle Morphology Characterization
   - Scanning Electron Microscopy (SEM)
   - Polarized Light Microscopy/birefringence
   - Hot Stage Microscopy (HSM)
   - Particle Size Distribution
Solid State FTIR Spectroscopy
Sorption Isotherm Analysis
Karl Fischer (KF) Analysis
Vapor Pressure Analysis
Heat Capacity Measurements
Solubility Relationships
Dissolution Rate Studies
Slurry Conversion Studies
Bioavailability/Pharmacokinetics