work performed with v.v. chernyshev, a.v. yatsenko, o.b. ryabova, v.a. makarov, c.e. botez, r....
TRANSCRIPT
![Page 1: Work performed with V.V. Chernyshev, A.V. Yatsenko, O.B. Ryabova, V.A. Makarov, C.E. Botez, R. Suryanarayanan, C. Nunes. See also poster #14 on R-albuterol,](https://reader035.vdocuments.net/reader035/viewer/2022062308/56649e605503460f94b5b121/html5/thumbnails/1.jpg)
Work performed withV.V. Chernyshev, A.V. Yatsenko, O.B. Ryabova, V.A. Makarov, C.E. Botez, R. Suryanarayanan, C. Nunes.
See also poster #14 on R-albuterol, S. Cuffini
Synchrotrons, Mannitol, Prazosin, etc.
Synchrotron radiation is accessible, decisiveHydrogen bonding affects molecular conformation
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Physical adsorption of Kr on graphite
X-ray diffraction of Kr on exfoliated graphite. Crystallography with one Bragg peak - Kr(1,0)
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Experiments at SSRL in 1979. (Moncton, Birgeneau, Horn, Brown, PWS)
20x better angular resolution
Substrate coherence length is ~2000Å
Completely new picture!
There is a disordered phase between the commensurate and incommensurate solids. Interesting new physics.Heroic age of synchrotron radiation.
Parasitic on high energy physics.
Huge investment of effort to get one or two weeks of access per year.
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National Synchrotron Light Source at Brookhaven National Laboratory
Produces electromagnetic radiation from IR to -rays.Easy to obtain access.
~75 experimental stations~2500 users per yearTypical of many facilities worldwide: APS, ESRF, SLS, SRS Daresbury, SSRL, …, which are eager for users.
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Synchrotron access is for:
Academic: Who publish in the open literature*
Industrial: Hold data for proprietary reasons**
The people who operate these facilities need to have them widely used!
* Access by writing competitive proposals or arranging collaboration.
** You have to pay for the prorated cost of operating the facility - ~$250/hour = $2000/pattern at NSLS.
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Form 1 -- Lab
Form 2 -- Lab
Form 1 -- S ynchrotron
Form 2 -- S ynchrotron
Compare lab vs. synchrotron data sets.This drug has two polymorphs that can’t be quantified except by
Rietveld.
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THEORY OF POWDER DIFFRACTION
UNIT CELL
RECIPROCAL LATTICE,SPACE GROUP
POWDER PEAK POSITIONS
POWDER DIFFRACTION PATTERN
CONTENTSOF UNIT CELL
PHYSICAL SAMPLEAFFECTS LINESHAPES
OTHER ARTIFACTS:PREFERRED ORIENTATION, ETC.
2)()(2~ jxyzhkli
jhkl efI
INTENSITIES
2 3 4 5 6 7 8 9 10 11 12 13 14 152 (degrees)
2 3 4 5 6 7 8 9 10 11 12 13 14 152 (degrees)
. . . . . . . . .
. . . . . . . .
. . . . .
. . . . . . . .
. . . . . . . . .
(series of elementary recipes)
INSTRUMENTAFFECTS PEAKSHAPES
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USE OF POWDER DIFFRACITON TO SOLVE A CRYSTAL STRUCTURE
2 3 4 5 6 7 8 9 10 11 12 13 14 152 (degrees)
1. Start with the best data you can get (but no better).
2. Get a list of accurate diffraction peak positions.
3. Figure out a lattice that explains the peaks.
4. Guess the space group (systematic absences, # molecules).
5. Search for the best place to put the molecule(s), best conformation of the molecule.
6. Refine, refine, refine, refine, refine, …
At any stage, you can be forced to jump back to any stage.
Data Chemical knowledge of contents
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Don’t think that people only use powders for organic molecules, or that direct space modelling is the only useful technique
Lausenite: SouzaliteFe2(SO4)3·5H2O (Fe,Mg)3(al,Fe)4(PO4)4(OH)6·2H2OJ. Majzlan, …, PWS A. Le Bail, …, PWSDirect Methods (EXPO) Real Space (ESPOIR)
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Analyzer crystal geometry measures angles – eliminates significant aberrations of familiar Bragg-Brentano diffractometer.
Capillary sample geometry is very helpful. Eliminates preferred orientation, peak shifts that bother flat plate
#1, 2 This is a data-driven enterprise. Students may think that we spend all our time talking about algorithms, software, etc., but the results are no better than the data!Powder diffraction station at X3B1 beamline, National Synchrotron Light Source, Brookhaven National Laboratory, U. S. A.
Ion chambersample
GE (111) analyzer crystal
Scintillation detector
MonochromaticX-ray beam
Si(111) double monochromator
From storagering
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#3. IndexingGiven some values of d spacings, find a lattice that fits them, i.e., find {A,B,C,D,E,F } such that every d can be expressed as
1/d 2 = Ah 2 + Bk 2 + Cl 2 + Dkl + Ehl + Fhk for some integers h, k, l.
Familiar programs, in the public domain:TREOR, ITO, DICVOL, have their quirks, but basically they always work, given sufficiently good data. (Often possible with good lab diffractometers, nearly always with synchrotron data.)
TOPAS (Alan Coehlo, Bruker AXS) has indexing tools that are qualitatively more powerful.
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Prazosin
Designer drug – selective antagonist for α1-adrenoceptors (blood pressure).
Four other polymorphs claimed in US Patents 4092315, 4739055, 4816455, and JP Patent 03206088. Department of Medicinal Chemistry, State Scientific Center of Antibiotics, Moscow, could not reproduce any of them.
Patent literature : LiteratureMilitary intelligence : Intelligence
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4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
0
10000
20000
30000
40000
50000
P ow der d iffraction pattern of prazosin H C l = 1.15019Åcom pared to peak positions from P D F 42-1864
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Four of the lines in the Powder Diffraction File for that compound are impurities, not seen in our pattern.
Throw them away and use TOPAS to index the lab data.
xxxx
TriclinicTOPAS FOM = 15.99a = 8.717Åb = 7.572Åc = 16.381Åα = 90.01°β = 72.43°γ = 108.95°Vol = 969Å3
(There is a lot of not-quite-good data in the data bases. Is not-quite-good distinguishable from bad?)
Errors 0.021° ± 0.024°
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Given sufficiently good data -> pattern can be indexed easily
Data quality = sample instrument
If a pattern from a good instrument* cannot be indexed, there is something wrong with the sample
*Test your instrument by trying to index known phases of comparable complexity. Acetaminophen and Ibuprofen are good organic test cases to get started.
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#5. Make a model of the molecule, put it into the lattice.Move the model around seeking best agreement between calculated and observed diffraction patterns.
Lots of options: software DASH, PSSP, FOX, TOPAS, PowderSolve, …
In this case, assumed P1, coauthor searched nine parameters with software developed with H. Schenk.
_Cl
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#6. Refine, refine, …If your presumed rough solution is close enough, you can roll down hill to the correct solution, using refinement programs such as GSAS, TOPAS, FULLPROF, …
2
~100 refined variables
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THE GLOBAL TOPOLOGY MAY LOOK MORE LIKE
THIS
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χ2 = 2.31, Rwp=5.92%. No restraints except for tethering all H atoms.
Any fit looks good on this scale
d = 1.47Å
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Monoclinic, Cc, χ2 = 2.78, Rwp=5.92%
Same steps for prazosin free base – only 6 search coordinates
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Planarity of the aromatic rings gives a measure of the degree of accuracy of the finished atomic geometry.
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Bonds Hydrochloride Free Base
N17-C18 1.489Å 1.521Å
C18-C19 1.509Å 1.491Å
C19-N20 1.513Å 1.507Å
N20-C21 1.471Å 1.489Å
C21-C22 1.538Å 1.610Å
C22-N17 1.472Å 1.543Å
Angles
N17 123.1 117.9
C18 102.3 107.7
C19 114.2 114.6
N20 115.8 111.0
C21 106.2 111.0
C22 105.1 102.8
Prazosin refinements. Geometry of piperazine ring
N17C18
Hydrochloride
Free base
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Hydrochloride3 N-H…Cl
Free base1 N-H…N 3.02Å1 N-H…O 3.02Å
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Prazosin conclusions:•That wasn’t so hard•Of relevance to quantitative modeling of structure-activity relationships
Hydrochloride
Free base
Hydrochloride methanol solvate (single xtl)
Prazosin2 tetrachloro-copper(II) (s x)
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The rest of the talk
1. Enalapril Maleate. Y.H. Kiang, Merck
2. Proxy for a real business problem.
3. Delta D-Mannitol
4. Mannitol hemihydrate
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Enalapril Maleate is a potent angiotensin converting enzyme (ACE) inhibitor with two known polymorphs, Form I and Form II. The single crystal structure of Form I has been known for almost twenty years. On the other hand, the crystal structure of Form II has never been reported before because of the difficulty to obtain single crystals of this polymorph, which is made by water slurry of Form I.
The crystal structure of Form II is of interest for several reasons:
1. Form II is the more stable of the two polymorphs.
2. The two forms are structurally similar based on X-ray, IR, and solid-state NMR.
3. The conformation of ACE inhibitors is important to their biological activity.
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5 9 13 17 21 25 29 33
Form I
Form II
Lab(Sealed Tube) and Synchrotron XRD patterns of Enalapril Maleate
2
=1.15Å,
4 9 14 19 24 29 34 39
2
Cu K1
Form I
Form II
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a=17.838
b=6.640c=11.64
9form I
a=33.987 b=6.642 c=11.210
form II
At the time of the original work, we couldn’t solve from simulated annealing. We could have benefited from the systematic geometric insights presented by Claire Gervais
23 parameters: 11 enalapril torsions (+2 maleate) + 6 orientation + 6 position
Enalapril Maleate
Monoclinic P21
Orthorhombic P212121
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Form I Form IIgreen:carbonyellow:nitrogenred:oxygen
Y.-H. Kiang of Merck found the solution by hand, using Cerius.
Y.-H. Kiang, Ashfia Huq, Peter W. Stephens, Wei Xu, Journal of Pharmaceutical Sciences 92, 1844-53 (2003)
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Real business problem:_____ has a patented polymorph of _____ , and suspects that _____ is selling material that infringes. It is desired to examine the commercial tablets and determine the polymorph of the API for potential litigation.
Proxy:Examine commercial tablet of Endocet 500/7.5Gross tablet 607 mgAcetaminophen 500 mg – known lattice & structureOxycodone (as HCl) 7.5 mg – pattern in PDF but lattice unknown,*
* In general, I’d like to get better info into the PDF database. Please get in touch if you can help.
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Endocet (in tact tab le t)500 m g Acetam inophen7.5 m g. oxycodone H C l
2 4 6 8 10 12 14 16 18 20
2theta (degrees)
0
20000
40000
60000
80000X
-ra
y In
ten
sity
(co
un
ts p
er
10
^6 m
on
itor)
Acetam inophen
data: endocet.631
M easured
Profile fitx 50 of acetaminophen
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Powder patterns of oxycodone hydrochloride from ICDD Powder Diffraction File. Strucutures and lattices are not known.
0 4 8 12 16 202 (degrees) a t = 0 .70Å
0
50
100
0
50
100
Pe
ak
Inte
nsi
ty
PD F 38-1799
PD F 06-0014
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Endocet (in tact tab le t)500 m g Acetam inophen7.5 m g. oxycodone H C l
3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0
2theta (degrees)
0
1000
2000
3000
4000
X-r
ay
Inte
nsi
ty
(co
un
ts p
er
10
^6 m
on
itor)
0
100
Oxy
cod
on
e H
Cl p
ea
ksfr
om
PD
F
A cetam inophen
data: endocet.631M easured P rofile fit
?
?
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Back to structures: Mannitol H H OH OH H H | | | | | | H - C - C - C - C - C - C - H | | | | | | OH OH H H OH OH
D-Mannitol (naturally produced in various plants)
Long-standing confusion about how many forms of D-mannitol exist – finally laid to rest by Burger, Henck, & co. (2000). (Their II, I, and III are more commonly known as α, β, δ)
α and β were solved from single crystals in 1968.
δ (lowest melting) identified in 1968, but no single crystals grown
(until ~2002, Henck & Benet-Buchholz, unpublished).
We solved the structure of δ from a powder sample (with 20% β)
Mannitol is widely used as an excipient in freeze-drying; metastable hydrate discovered by Lian Yu. TGA shows it is hemihydrate. Structure solved from powder sample with 26% δ, 2% β, ~10% ice.
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P 21 21 21
8.942 x 18.798 x 4.893Å205.6 Å3 / moleculeMiddle melting
P 21 21 21
8.672 x 16.875 x 5.560Å203.4 Å3 / moleculeHighest melting
P 21
5.089 x 18.250 x 4.917Åβ = 118.304°201.0 Å3 / moleculeLowest melting
Present work
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All the same steps. At extraction, we did a Le Bail refinement of the δ lattice along with Rietveld refinement of (known) β structure.
λ = 0.70224Å
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Alpha D-mannitol, H bonds(beta is very similar)
4-cycle
Zig-zag chain
![Page 39: Work performed with V.V. Chernyshev, A.V. Yatsenko, O.B. Ryabova, V.A. Makarov, C.E. Botez, R. Suryanarayanan, C. Nunes. See also poster #14 on R-albuterol,](https://reader035.vdocuments.net/reader035/viewer/2022062308/56649e605503460f94b5b121/html5/thumbnails/39.jpg)
One zig-zag chain
Delta D-mannitol, H bonds
![Page 40: Work performed with V.V. Chernyshev, A.V. Yatsenko, O.B. Ryabova, V.A. Makarov, C.E. Botez, R. Suryanarayanan, C. Nunes. See also poster #14 on R-albuterol,](https://reader035.vdocuments.net/reader035/viewer/2022062308/56649e605503460f94b5b121/html5/thumbnails/40.jpg)
alpha
beta
delta
The molecules in alpha, beta, delta D-mannitol are essentially identical
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Start with the best data possible?
Play the hand you’re dealt!
Mannitol hemihydrate
![Page 42: Work performed with V.V. Chernyshev, A.V. Yatsenko, O.B. Ryabova, V.A. Makarov, C.E. Botez, R. Suryanarayanan, C. Nunes. See also poster #14 on R-albuterol,](https://reader035.vdocuments.net/reader035/viewer/2022062308/56649e605503460f94b5b121/html5/thumbnails/42.jpg)
Int
en
sit y
(c ou nt
s)
2 (degrees)
(a)
(e)
(d)
(c)
(b)
-10
-8
-6
-4
-2
0
20 40 60 80 100 120 140 160 180 200
Temperataure (°C)
Hea
t fl
ow
(W
/g)
94
95
96
97
98
99
100
Wei
gh
t (%
)
120 140 160 180
Temperature ( C)
TGA
DSC
Lab x-ray (Minnesota)
Lab x-rays identify the sampleTGA -> hemihydrate
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6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44
Tw o Th e ta (d e g )
0
5000
10000
15000
20000
25000
No
rma
lize
d X
-ra
y co
un
ts
-2000
0
2000
Diff
ern
ce
da ta
fit
x5
H y d ra teD e ltaB e taIce
Index the peaks that are not any other identified phase to a triclinic lattice:9.896 x 10.542 x 4.786 Å, 102.59°, 86.09°, 116.08°, 2 mannitol in P1.
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A
B
Search two independent mannitol molecules, one O atom.Several different starts.
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Hydrogen bonding pattern in hemihydrate
Normal conformation
Conformation with one leg
lifted
water
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Only mannitol hemihydrate has an OH twisted up into the plane of the C-C-C-C-C-C backbone.
What is the energy cost relative to the conformation of all other observed mannitol crystal structures?
Is there no way to pack “table” mannitols and a water of solvation without straining the molecule?
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Structure determination from powders requires:Good dataFundamental understanding of the available toolsMotivation
Choose good problems.
If you are stuck with a crystallographic problem, try a synchrotron.* You pay taxes – claim your share. Find one where there is already a strong program of structure determination.
* Also single crystal.