X-ray pow­der dif­frac­tion - A pow­er­ful tool in the pharma in­dus­try

Dr Michael Caves, Malvern Aimil In­stru­ments Pvt. Ltd.

Chemical Industry Digest - - What’s In? - Dr. Michael Caves

De­scribes this tool, its cur­rent & fu­tur­is­tic ap­pli­ca­tions through this Q&A.

Why is X-ray pow­der dif­frac­tion (XRPD) so im­por­tant to the phar­ma­ceu­ti­cal in­dus­try?

XRPD is a pow­er­ful tool in the pharma in­dus­try be­cause of its ca­pa­bil­ity to help re­searchers iden­tify crys­talline struc­ture of ma­te­ri­als, iden­tify phases that are present, dis­tin­guish be­tween poly­morphs, and even elu­ci­date struc­ture in amor­phous ma­te­ri­als. Prov­ing that a new chem­i­cal en­tity (NCE) is in­deed a novel struc­ture is crit­i­cal to patent po­si­tion­ing. Ad­di­tion­ally, pow­der dif­frac­tion mea­sure­ments can be made un­der non-am­bi­ent con­di­tions (tem­per­a­ture, hu­mid­ity, etc) such that ma­te­rial sta­bil­ity can be tested un­der ex­treme con­di­tions. And most ap­pli­ca­tions of XRPD are non-de­struc­tive in na­ture, leav­ing the sam­ple in­tact for fur­ther in­ves­ti­ga­tion by other tech­niques.

What ad­vances in XRPD in re­cent times have been most sig­nif­i­cant for phar­ma­ceu­ti­cal anal­y­sis?

In the past five years, new op­tics, stages and de­tec­tors have al­lowed more ap­pli­ca­tion ca­pa­bil­ity to be added to a multi-pur­pose dif­frac­tion sys­tem, as well as im­proved the per­for­mance for even rou­tine types of mea­sure­ments. For ex­am­ple, new XRPD op­tics, such as PAN­a­lyt­i­cal’s Brag­gBrentanoHD op­tic de­liv­ers 40% im­proved sen­si­tiv­ity for ul­tra low-level poly­morph screen­ing. New ap­pli­ca­tions pos­si­ble on an XRPD sys­tem in­clude small an­gle X-ray scat­ter­ing (SAXS) for nano-sized ma­te­ri­als, which can de­ter­mine size dis­tri­bu­tion and shape of ma­te­ri­als in­clud­ing mi­celles, pro­teins, and nano-par­ti­cles for drug de­liv­ery; with new de­tec­tor tech­nol­ogy and easy con­ver­sion of an XRPD sys­tem to hard ra­di­a­tion (such as Sil­ver X-ray tube an- odes), pair dis­tri­bu­tion func­tion (PDF) for in­ves­ti­gat­ing the struc­ture of nano- and amor­phous ma­te­ri­als has brought this tra­di­tion­ally syn­chro­tron beam-line ap­pli­ca­tion to a lab­o­ra­tory sys­tem; and these same ad­vanced de­tec­tors for hard ra­di­a­tion lend them­selves nicely to com­puted to­mog­ra­phy (CT)on an XRPD sys­tem, to an­a­lyze non-de­struc­tively the in­ner struc­tures of coat­ings on tablets, eval­u­ate poros­ity and dis­tri­bu­tion of com­po­nents within tablets, and even in­ves­ti­gate tablets within pack­ag­ing.

What are the re­cent trends in XRPD that you have seen from the phar­ma­ceu­ti­cal in­dus­try?

We are see­ing a trend to­ward cen­tral­ized re­search labs when merg­ers have oc­curred. This in turn has caused an in­creased in­ter­est in XRPD sys­tems that can be used for mul­ti­ple ap­pli­ca­tions ver­sus ded­i­cated

sys­tems for a spe­cific ap­pli­ca­tion. So sys­tems com­bin­ing com­bi­na­to­rial screen­ing, en­vi­ron­men­tal cham­bers (heat and hu­mid­ity), SAXS, and transmission ca­pa­bil­ity are rou­tinely be­ing sup­plied to this in­dus­try.

What other tech­niques com­ple­ment XRPD?

XRPD anal­y­sis for poly­morph iden­ti­fi­ca­tion, struc­tural anal­y­sis, and nano-par­ti­cle size and shape is com­ple­men­tary to many tech­niques avail­able in to­day’s an­a­lyt­i­cal lab­o­ra­to­ries, not only for the in­for­ma­tion pro­vided but also be­cause it is non-de­struc­tive. Solid state NMR, spec­tro­scopies such as near in­frared(NIR) and Ra­man, and sin­gle crys­tal dif­frac­tion all pro­vide molec­u­lar and crys­talline struc­ture in­for­ma­tion that com­pli­ments XRPD data. X-rayFlu­o­res­cence (XRF) spec­troscopy de­ter­mines el­e­men­tal com­po­si­tion, and data can be used in an au­to­mated fash­ion within XRPD phase anal­y­sis to re­strict the search to only phases chem­i­cally pos­si­ble.

How can a pow­der x-ray dif­frac­tion sys­tem as­sist re­searchers do­ing pro­tein crys­tal­log­ra­phy?

The two main ap­pli­ca­tions that come to mind are pow­der dif­frac­tion for screen­ing sam­ples that will be taken to a beam line for struc­ture de­ter­mi­na­tion, and SAXS of pro­teins for size and shape de­ter­mi­na­tion. Screen­ing sam­ples headed for a beam­line can show the qual­ity of the sam­ple, whether it is a sin­gle phase, and can also al­low in­dex­ing to de­ter­mine lat­tice type and lat­tice pa­ram­e­ters of the ma­te­rial. The ad­vent of evac­u­ated beam­path SAXS cham­bers has also al­lowed for bioSAXS ex­per­i­ments on a mul­ti­pur­pose XRPD plat­form, to study for ex­am­ple the over­all size, com­pact­ness and ag­gre­ga­tion be­hav­ior of pro­tein mol­e­cules in the ir­na­tive state (crys­tal­liza­tion not re­quired), and even to de­ter­mine the 3D en­ve­lope struc­ture at a res­o­lu­tion of 1-2 nm. And a very new ad­di­tion to ca­pa­bil­i­ties on an XRPD sys­tem is in situ pro­tein crys­tal­liza­tion with our new com­puter-con­trolled transmission hu­mid­ity cham­ber.

What are up and com­ing XRPD tech­niques or ap­pli­ca­tions that would be of in­ter­est to pharma?

One ap­pli­ca­tion that we see sig­nif­i­cant in­ter­est from phar­ma­ceu­ti­cal re­searchers is pair dis­tri­bu­tion func­tion (PDF) anal­y­sis, which can be used to dis­crim­i­nate be­tween dif­fer­ent amor­phous or crys­talline phar­ma­ceu­ti­cal struc­tures. Pro­tein screen­ing and in­dex­ing for re­searchers in the area of pro­tein crys­tal­log­ra­phy, which is typ­i­cally done on sin­gle crys­tal in­stru­ments or at beam lines, is another area we see as a growth area for XRPD.

Fi­nally, we have ad­vanced soft­ware ca­pa­bil­ity now, which in­cludes us­ing a method known as par­tial least squares re­gres­sion (PLSR) to an­a­lyze XRPD data for things like % crys­tallinity with­out the use of an in­ter­nal stan­dard, keep­ing the method non-de­struc­tive. More de­vel­op­ments are in the works, and it is through close col­lab­o­ra­tion with phar­ma­ceu­ti­cal com­pa­nies that we are able to make many ad­vances in XRPD to ad­dress the needs of the in­dus­try.

For more de­tails, please con­tact:

Malvern Aimil In­stru­ments Pvt. Ltd. Naimex House, A-8 Mo­han Co-op­er­a­tive In­dus­trial Es­tate, Mathura Road, New Delhi – 110044

Tel : 011-30810244 Fax : 011-26950011

Email : delhi@aimil.com

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