In pharmaceutical development, it is not enough to know what your compound is – you must also know which form it is in. Many active pharmaceutical ingredients (APIs) exist in multiple solid-state forms : polymorphs, hydrates and salts. These forms can differ significantly in properties such as solubility, bioavailability, stability and manufacturability.
One of the most powerful techniques for identifying and differentiating between these forms is X-ray Powder Diffraction (XRPD).
Real-World Consequences of Polymorphic Changes
Several high-profile drug development programs have faced critical issues due to unexpected polymorphic transitions or salt disproportionation – all of which were investigated or resolved using XRPD for analysis.
| Drug | Company | Issue | Impact | Resolution |
|---|---|---|---|---|
| Ritonavir | Abbott Laboratories | Sudden emergence of Form II (a more stable polymorph) with reduced solubility | Market withdrawal and loss of bioavailability | Reformulated as a melt-extrusion tablet |
| Rotigotine (Neupro) | UCB Pharma | Crystallization in transdermal patches during storage | Temporary market withdrawal in US and EU | Reformulated and re-approved |
| BMS-986205 | Bristol Myers Squibb | Salt disproportionation: conversion to free base | ~50% drop in bioavailability | Controlled via formulation and packaging strategy |
| Prasugrel (Effient) | Eli Lilly and Co | HCl salt converted to free base under storage | Risk to bioavailability during late-stage development | Process controls and free base specification set |
| Paroxetine hydrochloride hemihydrate | Various generics | Difficulty reproducing hemihydrate polymorph | Regulatory delays and formulation inconsistencies | Reformulation using a more stable polymorph |
Why use X-ray Powder Diffraction (XRPD)?
In solid-state risk assessment, XRPD Analysis is often the first step, as it:
- Is a non-destructive technique.
- Distinguishes between crystalline forms with high specificity.
- Is Sensitive to small changes in structure; e.g. hydratio or salt-to-base transitions.
- Is Essential for polymorph screening, form selection and stability studies.
In some cases XRPD is complemented by techniques like Raman Spectroscopy, especially when depth profiling or microscopic analysis is needed (e.g. in the case of Prasugrel).
How Particle Analytical can help as Contract Laboratory
Controlling the solid form is essential to ensure your product performs consistently and gets to market safely. Particle Analytical as contract laboratory offers GMP-compliant X-ray Powder Diffraction (XRPD) analysis for:
- Identification and confirmation of polymorphic form
- Salt/hydrate/form screening
- Stability studies and form conversion risk assessments
- Regulatory documentation support
