How does X-Ray Powder Diffraction assist companies that are looking to develop products with ingredients that have poor solubility?
A number of approaches have been developed to improve the solubility of an active pharmaceutical ingredient (API) including particle size control and chemical modifications. The effect of particle size control methods using mechanical (jet mill, ball mill) and engineering (cryogenic, crystal engineering) techniques can be monitored using X-ray powder diffraction (XRPD). As crystallites approach submicron to nanometer size, diffraction peak broadening can be used to determine the average crystallite size and the peak profile shape can provide information about the size distribution. Using XRPD along with particle size analytical techniques of microscopy and light scattering allows processing conditions to be optimized. The ICDD® Powder Diffraction File™ (PDF®) has a crystallite size module for quick assessment of nominal crystallite size.
For over 75 years, XRPD has been using PDF databases for phase identification of crystalline materials. A change in crystal structure (polymorph, salt, co-crystal) can have a significant impact on solubility and will result in a change in the powder diffraction pattern “fingerprint”. Extending beyond phase identification, XRPD is being used today to determine crystal structures when single crystal structure determination is not possible. Through a research grant ICDD currently sponsors a pharmaceutical project focused on determination of crystal structures from XRPD for large volume pharmaceuticals, adding over 85 new entries to the PDF.
What features and/or benefits does the current Powder Diffraction File offer that previous versions didn’t. What information is especially applicable to the pharmaceutical industry?
A recent addition to the PDF is the inclusion of amorphous diffraction patterns enhancing the analysis of XRPD data obtained from pharmaceutical formulations. An active area of pharmaceutical research centers around the generation of amorphous APIs, intended to improve solubility. Historically XRPD has not been used extensively to analyze amorphous materials as the resulting diffraction patterns typically are comprised of one to a few broad peaks. A number of excipients used in pharmaceutical formulations are also amorphous or nanocrystalline. With the increased use of whole-pattern-fitting (WPF) techniques for quantitative analysis by XRPD, access to reference diffraction data for amorphous phases is proving to be important. The PDF contains raw data diffraction patterns for many polymers used as excipients in pharmaceutical medications, as well as diffraction data for amorphous APIs that have been measured as part of the ICDD grant mentioned previously. The addition of raw data patterns extends beyond pharmaceuticals as other commercial polymers and disordered clays have also been added to the PDF, as their diffraction patterns cannot be modelled using known crystal structure parameters.
Can pharmaceutical companies use the data found in the current Powder Diffraction File for their regulatory submissions? Does ICDD provide any guidance for pharma companies based on the data in the Powder Diffraction File?
Absolutely, data in the PDF can be used for regulatory submissions. The Powder Diffraction File is the only crystallographic diffraction database that is ISO 9001 certified. That means we have a quality management system standard in place intended to help ICDD meet the requirements of our customers. This certification is awarded only after passing an annual external audit. Another important component of the PDF databases is the data entry quality system. ICDD is unique in assigning quality marks to every entry in the PDF databases, which are assigned based on editorial review of the diffraction data.
ICDD has taken a proactive role in advancing XRDP analysis of pharmaceutical materials, sponsoring a Pharmaceutical Powder X-ray Diffraction (PPXRD) symposium where practitioners of XRPD meet to discuss current trends in diffraction analysis of pharmaceutical materials.
In addition to presentations by technical leaders in the field of XRPD, these meetings have also included patent and regulatory attorneys that provide attendees with insight when considering how laboratory studies are applied to regulatory requirements. The next PPXRD meeting is in Hyderabad, India, 18-20, August 2017.
Another way ICDD contributes to the XRPD community, is by providing open access to the presentations of the PPXRD meetings (http://www.icdd.com/ppxrd/ppxrd-presentations.htm) along with another useful resource Advances in X-ray Analysis, the proceedings of the Denver X-ray Conference, (http://www.icdd.com/resources/axasearch/register_axa.asp.)
Looking ahead, are there other types of diffraction data or analysis that you are planning to include in future versions of the database. If so, how will these updates be of benefit to pharmaceutical companies and their drug development efforts?
For the next release of the PDF-4+ database, there will be over 14,000 new entries. ICDD extracts data from the literature, provides grants to researchers, and has collaborative agreements with other database groups that all contribute to the growth of the PDF. The addition of more APIs and excipient diffraction data will help pharmaceutical scientists stay current in XRPD phase analysis.
Many of the new features and improvements added to the PDF are the result of input from PDF users and ICDD members. Upcoming features that will benefit the pharmaceutical companies include more data file formats and images that can be imported for analyzing two-dimensional detector diffraction data, adding more bioactive subclasses to enhance focused phase identification searches, expanded bond length table data for assessing nearest neighbor atom distances, and a microanalysis feature that will allow the user to import X-ray fluorescence and energy dispersive spectroscopy data for inclusion in search match analysis. With powder diffraction analysis of pharmaceuticals using synchrotron radiation becoming more routine with mail in services, the ICDD PDF has adapted by including options for simulating synchrotron XRD patterns and increasing the intensity range allowed for PDF entries as more low-intensity diffraction peaks are being reported with synchrotron diffraction data.
Tom Blanton worked for Eastman Kodak Company achieving the position of Senior Principal Scientist. A member of ICDD since 1987, he served as Chairman of the Board of Directors 2008-2012 and was elected a Distinguished Fellow in 2013. He joined ICDD as Database Manager in 2013, became Principal Scientist in 2014 and was named the Executive Director in 2017.