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