X-ray powder diffraction began life as a specialised piece of kit requiring expert skills; now its use in the pharma industry has evolved and its application is increasing, argues PANalytical’s Dr Detlef Beckers
For many years X-ray powder diffraction (XRPD) has fulfilled several essential functions within the pharmaceutical industry. With its ability to identify the specific crystalline structure of compounds, the technique is used to provide structural information to patent applications and provide key data to support regulatory submissions and new drug applications (NDAs). However, the XRPD technique is currently under-exploited.
As a complex scientific discipline in its own right, X-ray diffraction has often required expert operation. Scientists with the specialist skills required by the pharmaceutical industry, such as formulation development and biological synthesis, may not have the necessary experience in XRPD. It is therefore understandable that its development into new areas of research within the pharmaceutical sector has been somewhat restricted.
Offering fundamental advantages over alternative methods, the benefits of the technology within the pharma arena are extensive. A non-destructive technique, XRPD elucidates structural details, allows the analysis of final dosage forms and enables the detection of low amounts of crystalline impurities and morphological changes during production. It enables the physical characterisation of organic compounds and their polymorphs as well as complex modern formulations.
accessible XRPD
Technical breakthroughs in instrumentation and advances in processing software have helped to bring a new generation of XRPD systems to market that are designed to address the specific requirements of multi-disciplinary environments. The advent of high-performance, ultra-fast detectors has improved detection limits and considerably decreased measurement times, while advanced software can easily handle the large amounts of rapidly generated data.
The introduction of innovative designs that house the instrument’s sample changer outside the radiation enclosure now allows the safe introduction of samples without interrupting workflow. The flexibility afforded by this type of walk-up functionality, coupled with intelligent software and user-friendly interfaces have made XRPD accessible to scientists and technicians with no specialist know-ledge of X-ray analysis.
Of course, to be useful within a pharmaceutical environment, any new XRPD system must support 21 CFR part 11 and accommodate all standard operating procedures, as well as meet the requirements for validation protocols of analytical instruments. Integration with LIMS and the ability to operate in the GLP and GMP environment is also essential.
With these advances, the complete range of analytical methods expected from a professional XRPD solution, including sample identification, quantitative and semi-quantitative analysis of compounds and crystallographic characterisation, are now practical within any pharmaceutical r&d environment.
formulation selection
Within the pharmaceutical industry, the selection of a compound, or active pharmaceutical ingredient (API) for development is a competitive business. To maintain intellectual property rights it is necessary that any and all possible permutations of the compound be included within the patent application. For this to happen, pharmaceutical companies must produce and fully characterise all possible polymorphs of the original compound.
XRPD is a particularly effective tool for fingerprinting different phases or polymorphs by their unique diffraction pattern (see Figure 1). Although general powder diffraction patterns can be used to determine a material’s crystal structure, in most cases alternative polymorphs can be characterised through the more straightforward identification of lattice type and unit cell dimensions.
Further information such as co-ordinates of atoms within the unit cell, site occupancy, displacement parameters and preferred orientation can also be obtained for a given sample.
XRPD is used successfully in determining crystalline composition, excipient compatibility and percent crystallinity of the components in a dosage form.
Crystalline composition affects properties such as solubility, bioavailability and stability. Therefore, following selection, the development of a polymorphic form or specific salt of an API requires complete control of crystallographic consistency throughout. Additionally, it is essential to determine and quantify polymorphic impurities. A full-function XRPD system enables the complete crystallographic characterisation required for this level of control.
The non-destructive nature of XRPD also makes it suitable for systematic pre-formulation studies for testing drug-excipient compatibility. The success of a drug formulation relies as much on careful and selective evaluation of drug excipients as it does on judicious discrimination of the active compound.
Excipient interactions are critical to the consistent release and bioavailability of the API. Developers need to be able to fully understand and control this behaviour to avoid potential costly late stage problems caused by formulation instability.
XRPD enables optimisation of pharmaceutical process parameters and production control. It can be used to assess the percent crystallinity and morphology of a drug’s constituents during manufacture. As such, it can be used to routinely monitor batch/dosage uniformity and to ensure final product stability.
The percent crystallinity, or volume concentration of, for example, an amorphous filler or active ingredient to a crystalline matrix within the drug’s dosage form can affect a drug’s pharma-cological performance as well as its processing behaviour. Additionally, any change in the morphology of fillers or in the crystalline state of active ingredients in the final product, as a result of the manufacturing process, can influence a drug’s bioavailability.
XRPD facilitates single measurement analysis of both the percentage of the API in the drug and the percentage of any amorphous or crystalline packing ingredients used. The latest XRPD detectors have a very low limit of detection for crystalline minority phases, in some cases down to 0.05Â%. This makes it applicable to many specialist applications such as the identification and quantification of small amounts of crystalline aerosol drug delivered by a pressurised metered dose inhaler (Fig. 2).
Because XRPD allows the direct investigation of materials under the conditions in which they are used in specific applications, it is an ideal tool for monitoring production. High quality quantitative data can be obtained without any special sample preparation method or equipment.
By monitoring the influence of tabletting pressure on the properties of finished tablets, for example, it is possible to determine the range of pressure associated with stable structural parameters. This allows the optimal pressure for the drug’s target dissolution rate to be assigned (Fig. 3).
the future
The ability of XRPD to determine structural parameters, together with its capacity for non-destructive analysis, encourages its use in diverse applications. Having established the ability to produce high quality XRPD data without the need for expert operational skills and within the constraints of a strictly regulated pharmaceutical environment, instrument manufacturers such as PANalytical have opened up the possibility for interdisciplinary development in applications such as the analysis of macromolecules and drug delivery system evaluation.