Synchrotron powder diffraction for the characterization of pharmaceuticals

speaker Dr. Gracilla Diaz deal from Univers Los Angeles in Venezuela and she's going to make the presentation singleton powder defraction for the characterization of pharmaceuticals. So we're very glad to have you with us. Dr. Garcia, the floor is yours. >> Thank you very much Karolina. I'm going to share my screen. Start sharing my screen. I hope you can see it. Presentation is preparing now. We can see it. But uh in presentation mode okay >> I think it's opening then now we can see it in presentation mode. Thank you very much. You can get ahead. >> Okay. But I don't see it. I don't know why. We just uh >> sometimes with F8. >> Okay. >> It can be shared as well. >> Okay. Yeah, I went to to the other screen. >> Okay. I think I now I can see it also. >> Fantastic. Go ahead, please. >> Yeah. Thank you very much, Karolina. It's a pleasure for me uh to participate uh this time um as an instructor in this very prestigious school. I will try to to summarize a little bit of uh what we need to uh to keep in mind for uh polit of a lamp. um award uh as a fast team some years ago. Uh but first I would like to acknowledge uh my collaborators, my closest collaborators, professor Miguel Delgado and Professor Analio Dugarte from the University from University Los Angeles here in Venezuela. Dr. Robert Toro and Professor Jos Antonio now from Univers Industrial Deantere in Bucharam Colombia, Andy Fish and Kathine De Joy from ESRF in France and Jakov and Distri from Avanguard uh in Germany. I think we have been working as a very good team in recent years and uh we are all very glad to be to be able to to share some of the work that we have been doing recently. Okay. And uh also because uh it's the first time that uh I make a presentation of this type, I will just uh like to show you very briefly where I am located. Um I am uh in Merida uh far from the capital actually closer to the border with Colombia. Merida is one of the oldest states and the university uh is has three campuses and the main campus is in Merida. It has two other campuses in in the in the other Andian states of Venezuela. The city is in a race valley at about uh 1,600 meters above sea level and we have um usually we have a little bit snow in the mountains and uh this is a uh view of the of the city. erh the city the university started as a seminary in uh 1785 and later became a university in 1810 soon after the declaration of independence and then it became universes. Our faculty of sciences was founded in 1967. Uh this is a view of the building and uh some of the mountains and uh our lab starts uh here uh from here. Uh so we have a I think we have a good laboratory space. Our laboratory was founded in 1969 and since then we have been um trying to carry out the best possible work with the with the resources uh available um uh to us. Uh the university is not the city is not only a university city but it's also very touristic uh place. It's very uh well visited by uh Venezuelans and uh people from abroad. And one of our major attractions is the highest and the second longest cable car system in the world. And this is some of the h typical views that uh we enjoy around here. mountains with a little bit of snow and the very emblematic uh Spelleladia plant that it uh grows above 3,000 mters uh in this uh region. Okay. So I I would like to start by pointing out uh four milestones in X-ray defraction. Of course we can uh think about uh different uh many different contributions uh but uh we think that uh there are basically four milestones that that need to be um that that need to be uh remembered. Uh first of all of course the discovery of X-rays in 1895 by William Conrad Rangan who obtained the Nobel Prize in physics uh for his discovery. The second one, the discovery of X-ray defraction by crystals in about 1912. Um, this was an experiment carried out by Walter Fredick and Paul Nippen. Uh, but the the experiment was suggested uh by Maximon Lae. Maximum Lowi received the Nobel Prize in chem in physics but uh he shared with Fredick and Nippen uh because of uh they they did uh a very nice uh experimental work. Certainly a major contribution was the defraction by single crystals uh uh made by the by William Henry and William Lawren father and son that also made them um recipients of the Nobel Prize in physics uh this time in 1915 and uh pretty much at the same time around 1916 in Europe Peter Dubai and Paul Sher and in the US Albert Hall developed the the methods for powder defraction uh using X-rays. This is a very very important contribution because uh of the um the nature or or the the application that powder diffraction has had over the years uh in uh the characterization of materials and we are going to emphasize in this uh talk uh some of the most important aspects uh of this uh of this technique. Let's first remember that what uh we consider to be crystalline materials. H for a crystalline material we need a periodic a regular arrangement of atoms and molecules h in some kind of repetition pattern in three dimensions. Uh we call conventional crystalline materials to those uh compounds that have a regular and periodic arrangement of those uh atoms and molecules. When we have an irregular and a periodic um arrangement of those motives, we have the so-cal amorphos materials. There is a very important group of materials that are regular but aperiodic among which we find the quasi crystals and Dan Shengman received the Nobel Prize in chemistry in 2011 uh because of the description of this uh of these materials. uh but we are not going to uh uh talk about this uh type of compound which are very interesting but we are not uh going to deal with them in in this talk. So basically what uh we have or what we uh would like to have is uh some kind of a structural motive which could be atoms or molecules or a complex an organometallic complex that is repeated according to a particular pattern that is called the crystal lis and uh to obtain a regular arrangement of those motifs atoms or molecules in three dimensions that uh that arrangement can be uh described uh in terms of a small parallel pipet which is called the unit cell. Erh that uh when we reproduce that uh small unit with a a a unit that uh is characterized by the smallest volume possible and the highest symmetry possible. when we repeat that uh that unit in three dimensions we uh reproduce the complete um crystal structure. So um in traditionally in we consider crystal uh conventional crystalline materials those materials that are that have a con constituent atoms or ions or molecules in a regular and periodical three-dimensional arrangement in the in the space. uh in and in that uh arrangement we uh define what is called a unit cell that is uh described in terms of uh three vectors and the angles between them and when we repeat this basic unit we uh reproduce the whole crystal structure. Erh one way to understand the interaction of X-rays and actually the radiation with uh an arrangement of this uh kind is uh through the interpretation that Bra that William Lawrence Brah gave to the defraction phenomena. Of course there is a very formal and very um more um elaborate uh erh ways to to present this but uh I think for the purposes of uh this talk and for a a general understanding of the of the subject uh the brack interpretation is very very convenient. So what uh Brack proposed, William Lawrence Bra proposed was that uh if we have a a set of um X-rays of X-ray beams that um are in interaction with the planes, crystalline planes that we can define in the in that unit cell. Uh they will be defracted or in a similar way as a reflection of light by a mirror. they can be they will be reflected with the same um angle of incidence. H then we we can register that um reflected uh beam. Uh but at the same time there are many other erh rays that are um interacting with the same uh with with that particular set of planes. So um some of them will be in phase partially uh in phase or completely out of phase. The for those h emerging beams that have a path difference which is an integer integer number of the integer multi multiple of the wavelength then we have met the defraction condition. those uh rays will be in phase and we will produce a a reflection uh coming from that particular set of planes that are separated by a distance d we can see that h also in a simplified way here we have a set of planes of crystalline planes that uh are interacting with an x-ray beam that it's make to hit those particular planes with an ang at an angle of theta and when the the defracted beam emerges also at that theta angle we have a reflection. Those planes are identified with their millar indices HKL which are uh described in terms of the inverse of the intercept of that particular plane with different uh important crystalallographic direction in the in the in the structure. Here we have um an animation of what happens and uh we can see that when the the uh to obtain uh a reflection the H rays have to be in phase so that Bra's law is uh follow is obeyed depending on the way we have the sample we may have a single crystals or we have an aggregate of poly crystalline material. In the case of single crystal defraction, um we have just one fragment, one single crystal that uh we use um that uh we locate in the X-ray beam and uh a series of reflections from the different crystalline planes in that structure um are produced and registered in nowadays in uh 2D detectors. So we can have hundreds to thousands of reflections produced by the interaction of that X-ray beam. Actually can be also neutrons and electrons with a crystal that is been used uh in the experiment. In politraction we have an aggregate of a large number of very very small single crystals. And uh also we make uh we we use um an X-ray beam that uh interacts with the specimen now composed of many uh very small uh single crystals and um what uh what is produced is a one-dimensional or we what is registered at the end is a one-dimensional um erh result pattern resulting pattern which uh contains a few maxima and some of those maxima um may be superimposed with reflections from different uh sets of plane. So that's one of the main characteristics of the of the powder diffraction path. One way to understand the the defraction phenomena is the interpretation that was proposed by Peter Paul Peter Ael based on the in on the um construction of the reciprocal lis and the eel sphere and the idea that Bra's law is um obeyed is um holds under certain geometric conditions. For example, if we have uh the the the cartoon that we had in the previous slides where we have a set of uh crystalline planes and I apologize because uh this uh these names are are in Spanish but we have a set of crystalline planes identified by their indices HKL and we have an incident X-ray beam. We have a reflected beam at um the same theta angle. If we consider that the center of that sample is uh in a circle that is defined by the inverse of the wavelength that is used in the experiment then it can be shown mathematically here. I'm not going to um describe it in detail. It can be shown that uh every time that that emerging beam touches the circle which actually by rotation it can be made a sphere touches a sphere constructed in this way called the evil sphere then a brack law is obeyed and we obtain a a defracted beam that we can register with uh one uh available detector. So the idea is to to have a latis constructed h based on the inverse of the spacing between the different set of planes the so-called reciprocal lis and that lis in some way is rotated to make the different um planes um that describe that lattice touch the sphere of reflection and at At that point Bra's law is uh obey and we can see a reflection. So with the positions of those maxima the which are the the theta hkl we can calculate the spacing between the planes that are producing that particular reflection and we can from there we can calculate the unit cell parameters of our uh crystalline material. This is a another uh uh small movie representing uh how the different uh defracted uh X-ray beams are uh obtained when we bring the reciprocal lice to touch the surface of the H sphere constructed in the way that Eval proposed. So we have a characteristic pattern like this one that we register. This is actually a single crystal pattern but something similar happens uh in powder diffraction. Basically what we need is to have an X-ray source uh some gometer somehow of reflection. somehow a a detector uh and all these uh components um controlled by a system that can uh bring different crystalline planes to uh follow the defraction condition that is uh governed by by Bra. So that's the basic uh thing with the defractometry. H in that sense the direction of the beam is important because it will give us the size and shape of the unit cell and the intensity of the beam is important because it will it is related to the nature uh of the atoms and molecules that are producing that reflection and the special position um of of the different of the different atoms in those planes. So at the end that would be the way to obtain the crystalline of structure of that material. We have different types of resources the conventional old X-ray tubes uh more recent um sources as micro focus and different types of uh arrangements. Uh we have uh synretron sources. This is a view of serious synretron in Brazil and a view of ESRF in Grenobyl. And we have also some other emerging technologies like FELS that uh promise uh and have already demonstrated that are very useful in very um particular and important cases for the way to bring all the different uh planes uh to follow the defraction condition. we uh need somehow a a way to bring those planes and uh that's why uh there different uh geometries of gonometers have been devised. This is um these are two gonometers from uh different commercial uh vendors and but they use the brain geometry which is the most common one in in a laboratory setting for the synretron. Uh this is a view of uh the Hodgej at uh IBAM um ID22 beam line at uh Grenoval. And uh here we have uh a view of the of the defractoter, the detector, uh some uh device to uh for uh low temperature analysis, a robot to put the samples etc. Here, here we have a more recent view of this gonometer with a with a newer detector and we have uh here um an amplified view of the sample in a capillary mounted for synretron data collection. As for the detectors, we have uh point detectors, linear detectors that are useful, but uh of course they give a view a limited portion of the of the reciprocal space, but uh are um nevertheless uh useful. And we also have area detectors where uh we can collect in a more rapid way several reflections at the same time. H basically the information contained in a in a powder erh defraction pattern erh we can uh visualize it here. Erh first of all we have the position of the maxima which have to be recorded in the best possible way and are related to the unit cell the size and the shape of the unit cell that describe that uh the particular arrangement the particular crystalline arrangement of one or more crystalline components uh in the samp We also have the relative intensities of those reflections that is related to the type and the position of the atoms in the crystalline arrangement. We have the shape of the maxima that is related to the microructure. For example, the the different um crystalline domains changes in the shape due to tensions uh defects uh in the structure etc. And we have the background that includes a lot of uh information which is nevertheless uh important because it could indicate the the presence of um amorphous faces, the presence of diffuse scattering and other type of um low um crystallinity components. For example, uh one of the erh major problems uh that uh we can um that we can encounter when uh we use polifraction uh particularly the brament geometry is the it's the presence of several sources of errors and for structural determination from p diffraction the most important one is the preferred orientation and uh this is something that uh that needs to be uh taken well care of. Uh for example, in the preparation of the sample, a correct preparation of the sample and uh but and there is uh also ways to um to try to assess that uh through some different algorithms. Uh just to show a little bit of what um what it looks like if we have uh no uh preferential orientation in a sample which is uh the the ideal situation. Uh all planes are detected equally and we have a true registry of the a a good registry of the intensities of the of each reflection. However, if we have uh a preferred orientation, if the crystallites tend to orient in a particular way as it's shown here, then uh we could have um an effect on the intensities of uh certain reflections that come from different uh planes. So that's something that is very important and is very critical in braano geometry. Here uh just to to summarize some of the most important applications of X-ray powder diffraction. We have uh the identification of different crystalline faces in a sample. Quantification of crystalline faces and the structural analysis of uh different materials which has become more and more um erh easier to to carry out. uh because of uh different advances in instrumentation and in the programs uh that deal with this type of uh of information. So um the most common application of politraction is the identification of crystalline components of components in a poly crystalline aggregate. And uh in this case uh we have uh a very uh a nice review article uh in public defraction. Here is the the link um on the contribution of Albert Hall in the US. uh the most common application I mean it's it's very important to identify correctly the components of a poly crystalline aggregates and this is also a representation of that uh of that particular case for example we have for silicon dioxide several faces one is um amorphos and we have other faces with different crystal structures and the the power of the polraction methods is that uh it allows us to identify each crystalline phase because each crystalline phase has a characteristic pattern and also in a mixture of crystalline faces each phase produces a a particular pattern that is independent on the other fa phases. So it allows not only qual um identification qualitative identification but also quantification of the presence of those different components. The identification process uh can be summarized here. Each powder diffraction pattern is characteristic of a material. So it is a we can say that is a fingerprint and uh uh we can identify several basic steps. We have a search um of the defraction pattern uh usually in a database a superposition or inhouse or commercial databases. A superposition of that particular experimental pattern with a reference pattern that is found in a database. The identification deciding if the superposition of those patterns is appropriate and if they correspond to a a phase that is uh already um published and repeat the process for any other phases that are uh present and at the end if possible quantify the presence of uh each of the crystalline phases. For that we have uh very uh good databases uh in particular for powder diffraction. The PDF 5 plus database is the the database to use for the identification of materials. The Cambridge structural database contains mostly single crystal structural determinations but um powder diffraction patterns can be simulated from single crystal data and they can also be used in conjunction with the PDF5 uh plus database to identify materials. Uh there is also the COOD um database which contains a more limited number of phases and uh in some cases uh the quality of the of the patterns is is not uh uniform across uh across the database but uh it may be useful for some applications and for some uh researchers. So um the powder diffraction file is the the I would say this the the standard to use to identify a powder um poly materials in a poly crystalline sample and uh it started you know as a simple book as a simple registry by hand at the beginning and became um after 1978 as the ICD uh poly defraction file. As I mentioned before, the COOD er database is a open database that has uh very good patterns for some materials. Um and uh here is a summary. I'm not going to go into those details, but this is a summary of the power of the powder diffraction file for the characterization of materials and the Cambridge structural database uh which um even though it is a basically a single crystal powder defraction single crystal uh file or database can be used to obtain and here I have um highlighted the programs and the algorithms that are used in the that can be used in powder defraction. So the circular analysis uh using powder defraction data may uh involve for example the identification of uh known faces. H if we have erh after registering the powder diffraction pattern we can identify the crystalline phases using the powder diffraction file or or the Cambridge uh structural uh database or the ICSD also the inorganic chemistry database and uh if we have if we detect an isosstructural phase use that phase use the so-called SIF file in a in a structural refinement of that phase using several programs some of them are public domain and some of them are have a a cost but uh nevertheless they they are all important. Erh if we have unknown faces then we have to go through an indexing procedure using uh we we like uh dick pole um the the program uh dick bowl to determine the unit cell parameters then we need to do um having a step-by-step profile of the pattern do a pattern fitting and other decomposition procedures um we can use the several methodologies is there that are um properly um reference to. We need to um assign somehow study the systematic presence of reflections to assign the space group and uh we can carry out a structural determination process using uh different programs that use different algorithms for example Dash Expo Janna and other other programs that are available. the structural refinement usually uh by the rhythm method and uh using the programs that we mentioned before the structure refinement uh using a rhyth summarized here I'm not going to go into the the detail here uh because the lecture will be um recorded uh but uh this is uh basically what we have to do to obtain the unit cell the nature and the position of the atoms that will describe the crystal structure. Erh identify if there is more than one component. Identify the quantitative ratio of all those components and if um necessary if appropriate um study the microructure which is determine the crystallite size and any microructural defects that might have uh that might the the sample may have or the specimen may have. And here we have uh tried to combine or to present what would be the the workflow uh for um for a powder sample uh to go from sample preparation, a sample mounting either in a in a flat uh sample holder or in capillaries as it is used in mostly in the synretron and high resolution. synretron uh radiation collect the defraction pattern. I try to identify the faces using the available databases. If there are no entries on those databases, then we need to go through a an indexing profile feeding. uh try to use some uh previously known uh information on the on the molecule or use a geometry optimization programs to try to define um a structural model to start with. Go through a structural determination program process uh using uh different methods that are uh shown here. structural refinement and uh hopefully determine the crystal structure from posraction data visualization. There are several programs uh some are free, some are uh with the license uh for visualization, validation and the FD calculation is also very important and different uh software for analysis of the material like platon the mole that allow for example the assessment of whether the distances and angles that have been obtained in that structural determination procedure are valid or not they if they make sense or not and of course different types of uh studies for of intermolecular interactions. These are some key references uh some uh very important books uh that uh we need to keep in mind but the key reference is the volume age of the international tables for a x-ray for crystalallography. uh and here is a summary and outline of uh all the different parts. Uh so this is a very important and very key reference uh for powder diffraction. Uh there is also a very nice um review in nature review methods primers by a very uh experienced group of um powder defractionist. Okay. So I'm just going to use a few minutes to um to talk about some of the work that we carried out at uh ESRF at beamline ID22 with Andy Fish and Katherine De Joy between in October to December of 22 and in 2023. uh we receive a grant and Alio and I uh received a grant to through the LAMP uh project to carry out a study and we took to ESRF some of the problems that we had encountered in our uh daily work that we could not uh uh solve uh satisfactory with laboratory uh powder defraction data Just to remind what's the interest of pod defraction in the pharmaceutical industry at different points within in the erh research and development or in the production stages of a particular drug it is important to characterize it by different methods but x-ray defraction is very very important in the characterization of pharmaceutical compounds. uh for example from the R&D viewpoint uh at the laboratory stages we need to characterize properly the different active pharmaceutical ingredients determine if they if they present polymorphism if they are uh obtained as salts or hydrates or any other kind of sulfate um and any other uh structural um feature that may be important for the character for the characterization of that compound at the production level. It's also important for quality control of the of the drugs. H the analysis of the raw materials, the exipients, fillers, any kind of dice or any other type of uh additional material that will go into the formulation. We have to make sure that it's the correct uh a API and that exipients will not um erh transform the material into something that will be potentially harmful uh to the to the patient that is taking them. And uh the analysis of the commercial product, the final commercial product is also very important. It's and it's also carried out with uh among other techniques with X-ray powder defraction or with in general powder defraction erh to detect any kind of um changes in the API monitor the stability of the active pharmaceutical ingredient any kind of physical or chemical change in the product aggregation change in color for example which is not uh very uh not very uh good to have occur in a medication that we are uh using. Okay. Erh, it's also important to determine the illegal or counterfeit formulations uh something that is uh unfortunately common in in certain uh parts of the world. Uh and also erh problems with the patent infringement and things that have to be that have to do with the litigation processes uh because one company claims um to own the patent to that particular uh drug or formulation. And so it it could be also a complicated thing. that uh pol defraction actually is very important to uh try to solve those kind of problems. So one of the erh one of the er compounds uh one of the APIs that we studied that we took actually to the to the synretron to to try to h solve the problem that that we have in the structural determination was railene meilate which is a a compound uh used in the treatment of Parkinson disease. is very very common and for in Latin America in particular in Venezuela it's uh is very this uh drug is very common it's commonly used so it is marketed as the methylate salt and also as heartrate derivative but it's mostly formulated as the meilate salt we uh did a search in the Cambridge structural database and in the PDF4 organic database at the time. Now it is combining the PDF um database is combined um into uh organic and inorganic uh compounds but uh the search at the time indicated that uh there was one similar compound but it's not it was not the API that we had uh on hand and uh and it was a ethane dulfonate of railulene which is the active component of the formulation. And the powder diffraction file contain the calculated pattern from this uh from this uh entry of the CSD. A a search in the Google patents uh site indicated that there were uh two crystal forms reported for pasageline methylate and uh there were different experimental powder diffraction patterns that had no particular no no structural information that we could use to to uh characterize the material. Erh so here is a superposition of the different forms that have been uh reported. Uh there is a form one the the first two these two materials. This is the our experimental pattern and a form two uh which supposedly has this uh this uh powder diffraction patterns. But our material we can see that uh coincides uh better with form two. We h attempted uh struct determination using the laboratory data and using as a starting point the rasagulene fragment in the structure reported in the CSD and a methylate fragment that we found in a in a structure also reported in the in the CSD. After a poly feeding of the of the pattern and using dash erh we obtain a solution and the refinement of that uh of the uh atomic positions uh without including preferred orientation led to an incorrect structure. There was a structure determined kind of satisfactory based on the kaiquare profile here for example that is uh important to follow. uh but it require uh using or refining a preferential orientation parameter for the 004 plane which is uh which give the gave this value which is not not very good actually for the prefer preferred orientation parameter uh refine. We did the revel refinement anyway and we obtained um this uh final discrepancy factors which are not not too bad but uh the superposition with the uh structure minimized by DFT calculations. H gave um a value of uh RMS CD which is very important to uh determine if the structure is uh well determined or not. It is well below 0.35 which has been um described by uh Vantra and Noman as a good value but uh this actually showed that it was not the the correct structure. uh the readable refinement will uh uh resulted in this uh in these parameters using the DFT um erh minimize uh results and but we see that it's basically the same when we after collecting uh data at ID22 at the SRF this is the pattern or obtained and using the DFT erh model, the um energy minimize model with topas academic, we obtain a much better fit for the preferred orientation parameter and uh a good fit of the different uh discrepancy factors. And this indicated that in this case, this is just um a summary of the parameters. This indicated that we now have the the correct structure. we see that um the configuration at C1 is R and that this plane is actually planer in the model obtained with laboratory data there was a a slight um change in the position of one of these atoms. Uh so the configuration of this uh ring was not uh was not um the best one and the uh examination of the distances and angles with mogul, one of the programs uh included in the Cambridge structural database set of programs indicated that all the distances and and angles were acceptable were not uh out of uh what uh it is expected. with respect to other structures. The superposition of the experimentally determined structure with the synretron data and the energy minimized structure gave very a very good uh value and we can be confident that this was the correct structure. Other type of materials that we have studied are some anti-comvulsence in particular the derivative of valproic acid and um the commercial form usually contains a val a mixture of valproic acid and sodium valproate. However, there are some formulations that are used in several countries with other metal derivatives and we wanted to explore uh the structures of those compounds that have not been actually well characterized. So we prepare different uh compounds different derivatives of calcium, stronium, zinc and cadmium and we study the structure with by single crystal and also used um powder defraction at ID22 to see the behavior uh upon uh cooling the material. All these compounds have some common structural features and display we we saw that they displayed a very interesting uh behavior uh with temperature. So by single crystal uh x-ray defraction using um a silver source in the Benita universine burn um we detected that there were one monocleinic structure the material crystallizes as monocinic at room temperature with this uh structure and at low temperature as we lower the temperature the there is a transition to a tricleic phase with a smaller cell in between we studied uh we did this study at the SRF at ID22 in between there are certain it's a very very complicated behavior but we can uh kind of pinpoint a a temperature where we think that there is a a good possibility that This is uh the transition from one uh crystalline structure to another and uh we are in the process of uh completing this um this description because it's it's not easy. The the the behavior with temperature is very um it's very complicated and uh actually the other the stronium and uh cadmium materials are even more complicated than this one. Uh this is a setup uh in a capillary. We use the prior stream for capillaries that can go uh in this range and in this uh link you can see a very nice uh video of how it works and how the robot works. Actually um we also study the structure of Beriden hydrochloride a very complex compound that is also used in the treatment of Parkinson and one of the problems here is that there were no reports no previous reports of this structure. H we recorded laboratory data but uh uh even though we attempted to solve the structure it was not possible with laboratory data. There was a lot of uh prefer orientation h in the in the pattern but we successfully uh determine it uh from synretton data using direct methods and these are this is a view one view of the packing arrangement and um the work uh was done by uh Daniel Pimento at WIS in Bukaramanga Colombia and we have been collaborating in the uh study of this uh particularly different and difficult uh compounds. Here is a a graphic with the pattern obtained um with the laboratory source converted to synretron h scale and the pattern h from the synretron uh study and we can see that there is a much better definition of uh of the defraction maxima. We have uh we we see better some very small pigs and uh so we can uh better obtain we can obtain a better uh description of the structure because we can model uh in a much better uh way the preferred orientation. Erh this is another compound that we studied at ESRF Alisa PRE and uh in this case uh uh we also had uh we had a report in this case of a monoc clinic phase in the CSD but uh the experimental pattern was different and there was a lot of prefer orientation so it could not be solved with laboratory data but it was successfully solved with the synretron data collected at the SRF using direct methods also. And this is just uh a graph to show the pattern of the monoc clinic form and the pattern obtained with the laboratory in the laboratory in Colombia and the pattern obtained in the synro and from this um this pattern uh it was possible to determine the structure with very good uh indicators of uh of confidence there. So um just to just to finish um I would like to acknowledge the support of uh FAID and the Ministry of Science uh in Venezuela, the university and also EIC our collaborators there, the laboratory for um structural chemistry um at University Industrial Santandere in Colombia. We also would like to acknowledge the support of Cambridge crystalallographic data center for providing access to the Cambridge structural database through the FAR program. And more recently um we uh obtain also um access through the phase program of uh FIT uh to the ICSD uh database. uh our collaborators at uh Indiana University, Northwestern University and Porto and um the companies that have provided some of the APIs that we use in our studies. Uh here is a photograph of our collaborators and a picture of Analio and I with Andy and Katherine at uh at ID22 and some of the people have that have worked h in uh some of these uh particular materials. So thank you very much for your attention and I'll be glad to answer uh questions uh if there is uh still a little bit of time. Thank you very much Garcia for a very informative session on pelvic defraction and congratulations on the nice results. We have several messages uh congratulating you one special saying thank you for the inspiring and and well simplified academic talk on the on the entire subject highly appreciate it much. So I'm going to take a couple of questions and please let me know how would you like to uh respond. Here we have uh Pelix asking what is the free access software for analysis crystal phases in XRD? Which other software can be used in place of expert high score? >> Uh I'm sorry can you uh repeat the question Karolina? >> For sure it is in the chat. So Felix is asking what is a free access software >> for anal for analyzing crystal faces in in XRD and at the same time which other software can be used in place of expert high score. >> Okay. Well, there are several uh programs. For example, um Gas 2 is uh open access. It can be uh used uh you know uh freely. Erh dash uh also for um structural determination is uh uh now free of access. It used to be included in the Cambridge structural database set of programs but now it's free access. and um expo also from the group in Bar in Italy is also free access. So uh all these these programs there is an also fox erh these programs uh can be used uh uh free of access. Um erh of course the the the programs the the set of programs that are provided with the er different defractometers have uh a lot of uh many features that make the process more automatic easier to carry out. Uh for example the graphical interface. Um but there are also uh some uh resources available that that can be used uh erh freely by by the scientific community. >> Wonderful recommendation. Thank you. And Ahmed is asking does liquid crystalline material is a quasi crystals? If not what is the difference? Uh let's see uh liquid crystalline material if it is a quasi crystal. Um no um it is I mean it can be uh studied by by defraction techniques. It can be uh you know well described and represented. that uh in quasi crystals uh the the main thing is that uh you see a symmetry that is supposed to be forbidden by the conventional crystalallography. So in quasi crystals you usually have symmetries like five-fold symmetry 10fold symmetries that are uh supposedly forbidden by conventional crystalallography and that requires um more than one dimension uh more than three dimensions to describe it properly you know and that that's the complication but no no it's um it's not uh not necess necessarily the same thing. >> Great. We have a growing list of questions. Sakaria is asking how the organic derivatives explored well crystal crystallized prior to XRD measurements >> where and how the organic where and how the organic derivatives explored well crystallized prior to XRD measurements. Well, yeah. In many in most of the cases, we try different uh procedures. We try different solvents and different ways uh low temperature, high temperature, hydrothermal uh conditions for example to try to obtain single crystals. But uh these cases um these cases you know were not uh successful in producing single crystals of the quality appropriate for a single crystal um h study in in one particular the thing is that they may undergo trans phase transitions or they can uh produce a different polymorph for example in the in the meantime. So we we cannot be sure that what we started with is actually what we are studying uh at the end. So uh it it is a a little bit tricky but uh yeah we try many different crystallizing conditions and we unfortunately were not uh successful. >> Thank you so much Garcella. We have one last question I think because of the time and Felix is asking can you explain more on data visualization from XRD and what type of information can be visualized? What is the input data format? >> Okay. Um in general well different uh equipments and different uh vendors have uh some may have some different formats but uh in all the cases it can all be reduced to a what is called the XY uh format which is just uh a list I I I can uh post uh for example in the in the slidesh if you if you want to see that uh an example of that. So you have um a list of the pick positions and the intensity and uh most uh vendors uh of the equipment can the software can produce that kind of list that then can be used by different type of programs. >> Well uh Gracilla uh they cannot stop thanking to your presentation. Congratulations on a very nice and informative session. Uh if you can see in the chat there's couple of other questions that might be answered. They are also requesting for your presentation. So maybe you can follow up with the with the questions in the chat.