Presentation is loading. Please wait.

Presentation is loading. Please wait.

Polymorphs, Solvates and Phase Relationships: Some Perspectives Joel Bernstein Ben-Gurion University of the Negev DIVERSITY AMIDST SIMILARITY: A Multidisciplinary.

Similar presentations


Presentation on theme: "Polymorphs, Solvates and Phase Relationships: Some Perspectives Joel Bernstein Ben-Gurion University of the Negev DIVERSITY AMIDST SIMILARITY: A Multidisciplinary."— Presentation transcript:

1 Polymorphs, Solvates and Phase Relationships: Some Perspectives Joel Bernstein Ben-Gurion University of the Negev DIVERSITY AMIDST SIMILARITY: A Multidisciplinary Approach to Polymorphs, Solvates and Phase Relationships Erice, Sicily June 19, 2004

2 Polymorphs, Solvates and Phase Relationships: Some (Personal) Perspectives Joel Bernstein Ben-Gurion University of the Negev DIVERSITY AMIDST SIMILARITY: A Multidisciplinary Approach to Polymorphs, Solvates and Phase Relationships Erice, Sicily June 19, 2004

3 Some advice to lecturers I once read… “ People like to hear what they already know. Plan your talk so it contains about 35-45% of material your audience is already familiar with.” …but can’t remember where:

4 What is the current status of this field of research in polymorphs/ crystal forms/phase relationships?

5 Walter C. McCrone

6 Two landmark McCrone papers “Polymorphism”, in Physics and Chemistry of the Organic Solid State, Vol. 2, Wiley Interscience (1965), pp “Pharmaceutical Applications of Polymorphism”, (with J. Haleblian), in Journal of Pharmaceutical Sciences, 58, (1969).

7 The Current Status…? Meeting room for a conference on polymorphism ca Meeting room for a conference on polymorphism 2004

8 The three most important factors to consider when buying real estate: FLOCATION “Buy land; they’re not making any more of it.” - Will Rodgers

9 The three most important factors in doing research on crystal forms: FCONTROL

10 “If they haven’t defined and controlled their crystallisation experiments they can run into disappearing polymorphs.” “Roj” - Erice, June 15, 2004 “We’re going to talk about how you control crystal nucleation and growth…control at the nucleation stage.” Les - Erice, June 15, 2004 “Know what you have….Make the same thing every time.” Steve Byrn - Erice, June 18, 2004

11 Disappearing Polymorphs … it may be important to obtain a particular polymorph under controlled and reproducible conditions. However, this is not always easy to achieve. Tales of difficulties in obtaining crystals of a particular known form or in reproducing results from another laboratory (or even one’s own!) abound. Indeed, there are cases where it was difficult to obtain a given polymorphic form even though this had previously been obtained routinely over long time periods… Dunitz and Bernstein, Accts. Chem Res. 28, 193 (1995).

12 Disappearing polymorphs, cont’d... “…What is disturbing about the phenomenon of disappearing or elusive polymorphs is the apparent loss of control over the process: we did the experiment last week and got the result, and now we cannot repeat it! This kind of statement can lead to raised eyebrows or even to expressions of disbelief. We have ourselves experienced the frustration of not being able to reproduce an experimental result that was undoubtedly obtained earlier.”

13 Disappearing polymorphs: An old example: benzophenone

14 Schaeling gains control… ible to keep the metastable form open only in a room which was absolutely clean. It was almost impossible to carry out experiments on the metastable modification in a room which had previously “seen” the stable form, because the hands of [the experimenters] and the equipment in the laboratory were poisoned with the stable modification. The solution to this problem was to change the room and start the experiments once again from the start. Here in brief are some remarks about working with the meta- stable modification. It requires some practice. We observed that the metastable benzophe- none we obtained from the melt heated to a high temperature could be induced to yield crys- tals of the stable form only by introducing seeds of the stable form. The metastable form is very sensitive to the presence of the stable form. It was possi-

15 Disappearing Polymorphs: Benzocaine : Picric Acid Flow-melting (132ºC) form used as a pharmacopeial standard Fhigher melting ( ºC) form obtained by drying low melting form at 105 ºC for at least 1 hour or by vacuum drying/sublimation F Once latter form had been obtained, lower melting form could no longer be prepared

16 How the authors regained control... “As a matter of curiosity, it ought to be mentioned that once the stable modification was obtained, the metastable modification could no longer be isolated… It was found that after discarding all samples, washing the equipment and laboratory benches and waiting for 8-12 days, the low-melting modification could be isolated again. This has now been repeated several times in our laboratories.” Nielsen and Borka, Acta Pharm. Suecica 9, 503 (1972)

17 The Ritonavir Story

18 Ritonavir - The Problem  “…[the FDA] have seen similar problems before with other products.”  “…polymorphism…is the problem we’re experiencing with ritonavir…”  “After two-and-a-half years of closely monitored and tested…formulation manufacturing, we encountered a new form of ritonavir, a crystal form...Previous to [May- June 1998] we had manufactured about 240 batches of ritonavir and none of those batches had ever failed a dissolution test.”

19 Ritonavir - The Problem (cont’d)  “What has happened is that a new crystal form of ritonavir has appeared. Although it has the same purity, this form has different properties that make it more difficult to formulate. Specifically, the crystalline structure makes ritonavir dissolve more slowly…, which affects its bioavailability.”

20 Ritonavir - The Consternation  “There was no gradual trend. Something occurred that that caused the new form to occur…There was no early warning.”  “We, quite honestly, have not been able to pinpoint the precise conditions which led to the appearance of the new crystal form. We now know that the new form is, in fact, more stable than the earlier form, so nature would appear to favor it…Form II is new.”

21 Ritonavir - The Consternation (cont’d)  “We did not know how to detect the new form. We did not know how to test for it. We did not know what caused it. We didn’t know how to prevent it. And we kept asking the question, why now?…We did not know the physical properties of the new form…We did not know how to clean it, and we did not know how to get rid of it.”  “…our initial activities were directed toward eliminating Form II from our environment. Then we finally accepted that we could not get rid of Form II. Then our subsequent activities were directed to figuring out how to live in a Form II world.”

22 Ritonavir - Attempts to Resolve the Problem  “While we have speculated on the cause of this chemical transformation, we don’t have conclusive proof what happened…Abbott could not solve the problem for reasons which now are more apparent than they were when the problem was first discovered…Thermodynamics govern everything we do in the pharmaceutical industry.”

23 Ritonavir - Attempts to Resolve the Problem  “This is why all of us at Abbott have been working extremely hard throughout the summer, often around the clock, and sometimes never going home at night. We have been here seven days a week and we will continue to do so. We have canceled vacations and asked our families for their understanding and support. This is not an issue that we take lightly.”  “There were several sub-teams of three to 600 people per team working full time in different areas. We also called on as many resources as we could.”

24 Ritonavir - More attempts...  “We tried everything. We conducted countless experiments. We reconditioned our facilities. We rebuilt facilities and new lines. We looked at alternative sites. We visited a number of [other] organizations around the world…to see if we could start clean in a new environment free of Form II.”  “In a matter of weeks – maybe five or six weeks, every place the product was became contaminated with Form II crystals.”

25 Ritonavir - Incredulity and Unpredictability  Q: You are a large multinational company. Your scientists are obviously smart. How could this happen? A: A company’s size and the collective IQ’s of their scientists have no relationship to this problem…This obviously has not happened to every drug. But it has happened to other drugs.

26 Ritonavir - The solution proposed

27 Ritonavir - The solution approved Abbott Laboratories Receives U.S. FDA Approval for Reformulated Norvir (ritonavir) Capsule New Soft-Gelatin Capsules Offer Non-Refrigerated, Twice-Daily Treatment Option ABBOTT PARK, Ill., June 30, Abbott Laboratories announced today it has received U.S. Food and Drug Administration (FDA) approval for Norvir (ritonavir) soft-gelatin capsules…Norvir soft-gelatin capsules require refrigerated storage between 36-degrees F to 46-degrees F until dispensed to patients… The approval of Norvir soft-gelatin capsules follows intense reformulation work at Abbott after an announcement in July 1998 that a new crystalline structure of ritonavir, which affected how the semi-solid capsule dissolved, would interrupt the production of Norvir semi-solid capsules.

28 The Ritonavir Story - The Ultimate Loss of Control?

29 Ritonavir - The Problem  “…[the FDA] have seen similar problems before with other products.” It’s not a new phenomenon, but every instance of multiple crystal forms is new and unique, and each case is one which we have to fully investigate, characterize, control and properly educate and inform the regulatory agencies.

30 Ritonavir - The Problem  “…polymorphism…is the problem we’re experiencing with ritonavir…” Problem? Perhaps…but also a challenge to our scientific imagination and acumen and an opportunity to improve properties and gain some intellectual property.

31 Ritonavir - The Problem  “After two-and-a-half years of closely monitored and tested…formulation manufacturing, we encountered a new form of ritonavir, a crystal form...Previous to [May- June 1998] we had manufactured about 240 batches of ritonavir and none of those batches had ever failed a dissolution test.” They didn’t predict it, they didn’t expect it and they didn’t want it. Caveat on the most stable form: If they had discovered this form before launch they may have abandoned the drug because of poor bioavailability.

32 Some ways to avoid this problem: F High throughput technology Morissette, Wu, Dova, etc. FCombination of computational and experimental exploration of “crystal form” space Gavezzotti, Price, Pulham, Davey, Leiserowitz, Boese, Brill, Henck, Griesser, etc. F Thorough characterization Yu, Reutzel-Edens, Griesser, Henck, Bugay, K&R Harris, Niemczyk, etc. Know your system thoroughly Bugay, Byrn, Clas

33 Acetaminophen/paracetamol (Tylenol®) Two well characterized forms: e.g. G. Nichols et al., J. Pharm. Sci. 87, 684 (1998). F Commercial Form I requires binders for formulation F Form II can be directly compressed but transforms to Form I

34 Acetaminophen/paracetamol (Tylenol®) “Recalculation of the lattice energetics…established that this third structure is actually too unstable to exist.” P. Verwer and F.J.J. Leusen, “Computer Simulation to Predict Possible Crystal Polymorphs”, Revs. Comp. Chem. Vol. 12, Wiley, (1998) pp

35 A Philosophical Digression “But not to be able to find something is no proof of its nonexistence.” J.-F. Revel and M. Ricard, “The Monk and the Philosopher”, Thorsons, 1998, p. 57. “If you repeat an experiment and only get one form, then you’ve got to do the experiment again.” “Roj” - Erice, June 15, 2004

36 Acetaminophen/paracetamol (Tylenol®) F Third form detected by microscopy Griesser, etc. A. Burger et al., Acta Pharm. Technol. 28, 1-20 (1982); P. Di Martino et al., J. Therm. Anal.48, (1997); M. Szwlagiewicz et al., ibid 57, (1999). F Third form calculated and predicted from a number of similar energy possibilities Gavezzotti, Price, Lu, Henck, etc. T. Beyer et al., J. Am. Chem. Soc. 123, (2001).

37 Acetaminophen/paracetamol (Tylenol®) F Third form produced by iterative high throughput technology Morissette, Wu, Dova, etc. M.L. Peterson et al., J. Am. Chem. Soc. 124, (2002). F Characterized by microscopy and Raman Griesser, Bugay F X-ray powder pattern closely matches one of the less likely but possible structures of Beyer et al. K. Harris, David

38 6.Paracetamol (Acetaminophen) Widely used analgesic drug Exists as stable monoclinic form and metastable orthorhombic form A monohydrate and two trihydrates recently prepared at ambient pressure A. Parkin, S. Parsons and C.R. Pulham, Acta Cryst. 2002, E58, P.A. McGregor, D.R. Allan, S. Parsons and C.R. Pulham, J. Pharm. Sci., 2002, 91,

39 But still have no way of predicting solvates and hydrates… …although we might look for computed and other forms using high pressure. Gavezzotti, Price, Katrusiak, Pulham

40 Paracetamol recrystallised from methanol at 0.6 GPa to give a new 1:1 methanol solvate F.P.A. Fabbiani, D.R. Allan, A.D. Dawson, W.I.F. David, P.A. McGregor, I.D.H. Oswald, S. Parsons, and C.R. Pulham, Chem. Commun. (2003),

41 Paracetamol recrystallised from water at 1.1 GPa to give a new dihydrate On decompression crystal dissolves rather than disintegrates - scope for isolation of dihydrate at ambient pressure?

42 But still have no way of predicting solvates and hydrates… …although we might look for computed and other forms using high pressure. Katrusiak, Pulham Some of these might be metastable at ambient conditions. Pulham, Yu, Henck, Davey, Leiserowitz

43 Can metastable phases be isolated? Recrystallisation of monoclinic paracetamol from ethanol at 1.1 GPa gives the metastable orthorhombic polymorph, recoverable at ambient pressure. much lower pressure than in Boldyreva’s study on powder (no grinding) and interconversion is complete kinetic barriers associated with interconversion reduced Or, more importantly, can we co-crystallise paracetamol and ethanol?!! demonstration that metastable phases can be prepared

44 4.Parabanic Acid Analogue of barbituric acid. Structural studies have shown that one of the oxygen atoms does not take part in hydrogen bonding. X. M. He, S. Swaminathan, B. M. Craven, R. K. McMullan, Acta Cryst., 1988, B44, 271. T.C. Lewis, D.A. Tocher, G.M. Day, and S.L. Price, CrystEngComm., 2003, 5, 3. "it is unlikely that additional polymorphs of parabanic acid will be readily found as persistent metastable forms." Calculations also identified seven other hypothetical structures that lie only 2-6 kJ mol -1 higher in energy than the known form. A recent computational study correctly reproduced the known experimental crystal structure as the global minimum in the lattice energy.

45 Ritonavir - The Problem (cont’d)  “What has happened is that a new crystal form of ritonavir has appeared. Although it has the same purity, this form has different properties that make it more difficult to formulate. Specifically, the crystalline structure makes ritonavir dissolve more slowly…, which affects its bioavailability.” Thermodynamics and structure-property relations Herbstein, Yu, Reutzel-Edens, Henck, Bugay, Niemczyk. Davey, Leiserowitz, Morissette, Ward, Byrn

46 Ritonavir - The Consternation  “There was no gradual trend. Something occurred that caused the new form to occur…There was no early warning.” Many discoveries of new crystal forms are serendipitous, and it is often difficult, if not impossible, to precisely recreate the conditions at the time of the formation of the new form.

47 Ritonavir - The Consternation  “We, quite honestly, have not been able to pinpoint the precise conditions which led to the appearance of the new crystal form. We now know that the new form is, in fact, more stable than the earlier form, so nature would appear to favor it…Form II is new.” -Nature does, in fact, “favor” more stable forms -Essentially restatement of Ostwald’s Rule of Stages Davey

48 Ritonavir - The Consternation (cont’d)  “We did not know how to detect the new form. We did not know how to test for it. We did not know what caused it. We didn’t know how to prevent it. And we kept asking the question, why now?…We did not know the physical properties of the new form…We did not know how to clean it, and we did not know how to get rid of it.” Detect and test: Reutzel, Griesser, Henck, Niemczyk, Harris, Bugay, Harris, David, Morissette, etc. Caused: ??? Prevent: Henck, Davey, Leiserowitz Physical properties: Herbstein, Yu, Reutzel, Griesser, Henck, Niemczyk, Harris, Bugay, Harris, David, Morissette, Byrn, Erk, Schmidt, Ward, Nassembeni, Clas, etc.

49 Ritonavir - The Consternation (cont’d)  “We did not know how to detect the new form. We did not know how to test for it. We did not know what caused it. We didn’t know how to prevent it. And we kept asking the question, why now?…We did not know the physical properties of the new form…We did not know how to clean it, and we did not know how to get rid of it.” Why now? Nobody knows How to clean it; how to get rid of it: Henck, Davey, Leiserowitz

50 Ritonavir - The Consternation (cont’d)  “…our initial activities were directed toward eliminating Form II from our environment. Then we finally accepted that we could not get rid of Form II. Then our subsequent activities were directed to figuring out how to live in a Form II world.” “…how to live in a Form II world”: Herbstein, Yu, Henck, Davey, Leiserowitz, Bugay, etc

51 Ritonavir - Attempts to Resolve the Problem  “While we have speculated on the cause of this chemical transformation, we don’t have conclusive proof what happened…Abbott could not solve the problem for reasons which now are more apparent than they were when the problem was first discovered...” It took them a year to learn what you have learned in ten days

52 Ritonavir - Attempts to Resolve the Problem  “While we have speculated on the cause of this chemical transformation, we don’t have conclusive proof what happened…Abbott could not solve the problem for reasons which now are more apparent than they were when the problem was first discovered…Thermodynamics govern everything we do in the pharmaceutical industry.” Thermodynamics… Herbstein, Yu, Henck, Reutzel, Griesser, Katrusziak, Pulham, Davey, Leiserowitz, Byrn, Coquerel, Descamps Tell that to your second year chemistry/pharmacy students!!

53 Ritonavir - Attempts to Resolve the Problem  “This is why all of us at Abbott have been working extremely hard throughout the summer, often around the clock, and sometimes never going home at night. We have been here seven days a week and we will continue to do so. We have canceled vacations and asked our families for their understanding and support. This is not an issue that we take lightly.” We’ve also been here seven days a week, but (fortunately!) won’t continue to do so.

54 Ritonavir - Attempts to Resolve the Problem  “There were several sub-teams of three to 600 people per team working full time in different areas. We also called on as many resources as we could.” Now they can hire all Erice Poly 2004 as consultants!

55 Ritonavir - More attempts...  “We tried everything. We conducted countless experiments. We reconditioned our facilities. We rebuilt facilities and new lines. We looked at alternative sites. We visited a number of [other] organizations around the world…to see if we could start clean in a new environment free of Form II.”  “In a matter of weeks – maybe five or six weeks, every place the product was became contaminated with Form II crystals.” If they had thought more carefully about seeds they might have avoided at least some of these problems.

56 Ritonavir - Incredulity and Unpredictability  Q: You are a large multinational company. Your scientists are obviously smart. How could this happen? If their scientists had attended “Diversity amidst Similarity - Erice Poly 2004” maybe they wouldn’t have gotten into this mess…

57 Ritonavir - Incredulity and Unpredictability A: A company’s size and the collective IQ’s of their scientists have no relationship to this problem…This obviously has not happened to every drug. But it has happened to other drugs. And when it happens again, you’ll be ready…

58 The General Situation FWhat is the frequency of occurrence of polymorphism and/or different crystal forms? FHow do we prepare different crystal forms in a controlled and reproducible manner? FWhat are the similarities and differences of properties of the different crystal forms?

59 Occurrence of Polymorphism “…every compound has different polymorphic forms and…the number of forms known for a given compound is proportional to the time and energy spent in research on that compound.” W. C. McCrone, in Physics and Chemistry of the Organic Solid State, Vol. 2, Wiley Interscience (1965). Oft-quoted McCrone statement

60 Some “BUT’s” NaphthaleneSucrose Perylene red: Erk

61 Less quoted statement “With the accumulation of data there is developing a gradual realization of the generality of polymorphic behavior, but to many chemists polymorphism is still a strange and unusual phenomenon.” M.J. Buerger and M.C. Bloom, Zeit. Fur Krist. A96, 182 (1937)

62 Occurrence of polymorphism in molecular crystals F Not all polymorphs have structures reported; very often information is in primary literature as opposed to data bases F Problems locating all forms; definition by author(s) F Not always recognized F Statistics are difficult to determine F Existence of multiple crystal forms is not unusual

63 Occurrence of polymorphism in molecular crystals FThe existence of more than one crystal form (polymorphs and/or solvates) of any substance is not obvious and is not yet predictable. However, it is not surprising when new crystal forms are discovered, either by systematic searching, or by serendipity. F Keep eyes and mind open, even if not involved in a conscious effort to prepare new crystal forms.

64 The General Situation FWhat is the frequency or occurrence of polymorphism and/or different crystal forms? FHow do we prepare different crystal forms in a controlled and reproducible manner? Many suggestions from many speakers

65 Some suggestions for preparing different crystal forms in a controlled manner F Use thermal information from microscopy and DSC/TGA to determine trial conditions for crystal growth F Try kinetic as well as thermodynamic conditions F Use molecular and crystal structural data to generate crystallization conditions (solvent, solvent mixtures and ‘tailor-made’ additives) to prevent or induce particular forms F Avoid seeds of undesired forms, but use seeds of desired forms F Be aware of literature and use it F Don’t hesitate to use unconventional measures, e.g. pressure F If it works, it’s fair game F Potential for new technologies, e.g. combinatorial chemistry; high throughput technology

66 The General Situation FWhat is the frequency or occurrence of polymorphism and/or different crystal forms? FHow do we prepare different crystal forms in a controlled and reproducible manner? FWhat are the similarities and differences of properties of the different crystal forms?

67 Physical and chemical properties that may vary among polymorphs (partial list) Fmelting point Fvapor pressure Fhardness Foptical, electrical, magnetic properties Fcolor FIR spectra FNMR spectra Fmolecular conformation Fphotochemical reactivity Fthermal stability Ffiltration and drying characteristics Fdissolution rate Fbioavailability

68 Polymorphs are most often recognized because of the difference in properties… …but these properties can also be quite similar.

69 Melting point Benzocaine : picric acid a D-Mannitol b a J.-O. Henck, et al., J. Am. Chem. Soc, 123, 1834 ( 2001). Form I Form II b M. Burger, et al., J. Pharm. Sci. 80, 457 (2000) ºC ºC ºC 166 ºC

70 Similar IR spectra Two polymorphs of caffeine a a U. Griesser, personal communication

71 Structure-property relations Two strategies for studying structure-property relations: The number of variables can be minimized by studying polymorphic systems, since only the structure varies FMaximize the number of observations F Minimize the number of variables

72 Polymorphism in molecular complexes Two polymorphs of TMTSF and TCNQ Red FormBlack Form

73 Polymorphism and electrical conductivity of molecular complexes Two polymorphs of TMTSF and TCNQ Red Form Mixed stacks Black Form Segregated stacks

74 Comparison of Red and Black Forms of TMTSF:TCNQ Ffrom CH 3 CN by slow evaporation Ffrom CH 3 CN by rapid cooling of saturated solution; use seeds for larger crystals Red FormBlack Form F thermodynamic crystallization F transparent F mixed stacks F semiconductor F kinetic crystallization F opaque F segregated stacks F conductor

75 But there are limits… …another complex: Concomitant  and  polymorphs from benzene by F slow cooling F “prolonged slow evaporation”

76 Structures and electrical properties  Raise T of  form electrical conductivity rises by 10 7  - vertical stacks  - c-axis stacks offset FAlso upon formation of pellet  IR spectra identical before and after  no structural change by X-ray  ESR, SSNMR provide no clues

77 The “explanation”…. “…no ordinary conduction mechanism can rationalize the low resistivity value of the low resistance  form.” Goto et al., Bull. Chem. Soc. Japan, 69, 85 (1996).

78 Colors in “ROY” 5-Methyl-2-(2-nitro-phenylamino)- thiophene-3-carbonitrile  Differences in color can be accounted for from differences in conformation L. Yu J. Phys. Chem. A106, (2002) F Molecular property - can consider crystal as ‘oriented gas’

79 “Chromoisomerism” of 9-Phenylacridinium Hydrogen Sulfate F Red and green crystal forms P.H. Toma et al., Chem, Mater. 6, (1994). F Crystal structures carried out; other spectroscopic characterization

80 “Chromoisomerism” of 9-Phenylacridinium Hydrogen Sulfate FMany crystal forms recognized by difference in color. P.H. Toma et al., Chem, Mater. 6, (1994). F Diffuse reflectance spectra of powders, coupled with INDO calculations, did not identify the origin of the color difference. F “…it does not become obvious why one [polymorph] is red and the other is green. Chromisomerism in this case is just as puzzling to [us] as it was to Hantszsch and his colleagues 80 years ago… must consider collective interactions”. FEye is a sensitive detector; seeing is not necessarily understanding.

81 The General Situation FWhat is the frequency or occurrence of polymorphism and/or different crystal forms? FHow do we prepare different crystal forms in a controlled and reproducible manner? FWhat are the similarities and differences of properties of the different crystal forms?

82 Closing quotation… “There are many mysteries of nature that we have not solved. Hurricanes, for example, continue to occur and often cause massive devastation. Meteorologists can not predict months in advance when and with what velocity a hurricane will strike a specific community. Polymorphism is a parallel phenomenon. We know that it will probably happen. But not why or when. Unfortunately, there is nothing that we can do today to prevent a hurricane from striking any community or polymorphism from striking any drug.” Dr. Eugene Sun, Abbott Laboratories, 1998

83 “Many people think that polymorphism and solid state chemistry is the hardest thing to get right in drug development.” - Steve Byrn, Erice, June18, 2004 Closing, closing quotation

84 The End


Download ppt "Polymorphs, Solvates and Phase Relationships: Some Perspectives Joel Bernstein Ben-Gurion University of the Negev DIVERSITY AMIDST SIMILARITY: A Multidisciplinary."

Similar presentations


Ads by Google