New Drugs The US Food and Drug Administration (FDA) require submitters of an Investigational New Drug Application (INDA - new drug) to submit polymorph information.
New Generic Drugs The US FDA requires submitters of an Abbreviated New Drug Application (ANDA - new generic) that they must include a polymorphism study in order to demonstrate equivalence.
In addition, the International Conference on Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH harmonised Tripartite Guideline) ICHQ6A states that the following is required: Evidence that polymorphism is or is not exhibited by a new drug substance.
If polymorphism is exhibited, whether the different polymorphic forms can affect performance of the drug product, and what the potential for change is and how it might be controlled.
Drug Development "Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapour pressure, and density.
These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability.
Thus, polymorphism can affect the quality, safety, and efficacy of the drug product.
" [FDA guidelines].
In simple visual terms, the following scheme shows how to envisage polymorphism.
The Drug Substance is shown as a rectangle which can pack together in a crystal in different arrangements.
Each separate arrangement is a different polymorphic form.
It is believed that 50-80% of all Drug Substances exist in at least 2 polymorphic forms Polymorph A Polymorph B Each stage in drug development gets increasingly more complex.
After finding a potential hit in a screen, the early drug development phase of 'hit to lead' follows.
This 'lead' drug is then optimised and prepared for pre-clinical evaluation.
Drug development during the pre-clinical phase is designed to determine a drug's safety profile and prepare the drug for use in clinical trials.
During drug development, an initial scouting polymorph screen is designed to find a stable non-solvated form with good properties.
Phase 1 clinical trials are the first time during pharmaceutical development that the drug is used in humans to test safety and tolerability.
Larger Clinical Phase 2 studies assess how well the drug works.
This is followed by Clinical Phase 3 trials, the most expensive of all, to assess drug effectiveness.
Phase 3 drug development work includes a comprehensive polymorph screen find as many forms as possible in order to exhaustively cover the Intellectual Property space.
Continuous monitoring of the polymorphic form is needed throughout the whole drug development process in order to ensure consistent manufacture of the specified polymorph Analytical techniques are powerful tools employed during drug development: X-ray powder diffraction is used to provide unequivocal proof of polymorphism.
Other methods, including Thermal Analysis; Differential Scanning Calorimetry (DSC), Thermal Gravimetric Analysis (TGA), Hot-Stage Microscopy (HSM) and Raman spectroscopy are useful to further characterise polymorphic forms.