Solid-State NMR Utility in API and Formulation Process Development

1
Solid-State NMR Utility in API and Formulation
Process Development

• Robert Wenslow
• VP Business Development
• Crystal Pharmatech
• www.crystalpharmatech.com

2
Areas of Application
Organic Process
Engineering
Analytical
Biopharmaceutics
Bulk API Characterization In Formulation Samples
Produce Stable, Single Phase Bulk
Milling Issues
Compaction
Phys/Chem Stability
Spec. Justification
Processing Conditions
Solvent Stystem
Granulation
Tableting
In vivo performance
Excipient Interactions
3
Challenging Pharmaceutical Issues

• Salt Disproportionation
• Polymorphs
• Solvates and Hydrates
• Amorphous dispersions
• Motivation is regulation

4
Solid-State NMR
Molecular Tumbling
Orientation leads to CS difference
Rigid Solid
http//www.dur.ac.uk/resources/SSNMR/Training_cour
se_PH.pdf
5
Cross-Polarization (CP/MAS)
Decouple
Contact Time
(90)
1H
Detect
13C
Signal Intensity
Signal Buildup through dipole coupling (D)
Contact Time
J. Chem. Phys. 1973, 59, 569
6
Structure Disproportionantion
K-salt disproportionates in water to the free
acid 19F NMR was used to determine the
kinetics Fast experiments, quantitative
information Can also probe in formulation
7
Structure Salt Formation
Lower decoupling obscures Ns connected to
H Disappearance of 2 peak predicted Salt forms
at 3 Nitrogen Contact time can also be used to
discriminate
Useful information but long measuring times
8
Polymorph Quantitation
19F relaxation curves for I and II
19F NMR spectra of I and II
At 8.5 seconds FII shows zero signal 19F
relaxometry can be used
9
Solvate Identification
Peaks from EtOH
CP discriminates against the more mobile
regions DP discriminates against the more rigid
regions Spectral editing combination is powerful
to study solvates
Form II DP/MAS
Form II CP/MAS
Split CH3 indicates multiple environments
Straight forward measurements High information
content
10
API in Drug Product
L454 Freebase
19F SSNMR was used, measurements done at 5
oC Formulation API PEG 600 At 40 mgs/mL API
completely dissolved At 80 and 100 mgs/mL
shoulder observed
11
API in Drug Product
Expanded spectrum
Shoulder at 80 and 100 mgs/mL due to crystalline
freebase.
Rapid measurements, quantitative estimation of
solubility possible.
12
Amorphous API
1H NMR was used Rigid Gaussian Mobile
Lorentzian Fitting provides quantitation
Amorphous content 22.5 Extremely rapid
measurements, quantitative
No chemical shift resolution
13
Amorphous API
31P NMR
Amorphous has a very short T1 250 ms Crystal
had a very long T1 25 sec
Material stuck on pins 12 wt amorphous 10X
compaction at 200 MPa (RT) 5 wt 10X compaction
at 200 MPa (85 oC) 2 wt
14
Amorphous API
Broadening due to defects or phase separated
amorphous??
15
Amorphous API
M(tau)/M0 1-2exp(-tau/T1)
Each Phase in multi-phase system will yield
unique T1 value
16
Amorphous API
Monitoring in-process samples
Can detect amorphous content without any apriori
knowledge of system. Was also used identify
presence of multiple crystalline phases
17
Amorphous API
Monitoring stability samples

• Intensity directly proportional to amorphous
  content
• Qualitative amorphous content readily achieved
• LOD exceedingly low (limited only by NMR time)
• Quantitation requires calibration curve

18
DECRA
19
1H T1rho DECRA
Stability Sample
19F CP/MAS
Previous ID of multiple Phases by 1H T1rho Filter
Component 2 200msec T1rho 65 of total spectra
Component 1 39msec T1rho 35 of total spectra
DECRA
20
DECRA
Polymorph ID

• API process involves desolvation to get the
  anhydrous form
• Material forms amorphous on compaction
• A second phase observed in 19F SSNMR spectra for
  different batches
• Similar XRPD and DSC

19F CP/MAS
XRPD
Can we quantify second phase
21
DECRA
DECRA
19F CP/MAS

1H T1r DECRA
Component 2 6msec T1rho 20 of total spectra
Component 1 20msec T1rho 80 of total spectra
22
DECRA
Driving Process Definition
Wet milling in IPAc followed by Drying at 50 oC
recommended
23
DECRA
My API doesnt have a 19F
13C CP/MAS
T1rho Wt
Comp 1 133 70
Comp 2 55 30
1H T1r DECRA
Component 2 91msec T1rho 22 of total spectra
Component 1 193msec T1rho 78 of total spectra
24
Heteronuclear Dipolar Correlation

• 1H-13C, 1H-15N, and 1H-23Na HETCOR spectra for a
  hydrated API

13C
15N
23Na
1H
Correlations indicate atoms near in space (3 Å)
24
Cryst. Growth Des., 2006, 6, 2333-2354.
25
Amorphous Dispersions
26
2D 1H-19F Correlation

• 1H-19F CP-HETCOR easily proves molecular
  association on the lt 10 Å scale
• Experiments such as these take 1-2 hours to
  perform for typical drug loads (20-60 w/w)

500 ?s
Diflunisal
PVP
Solid amorphous solution
2 ms (spin diffusion)
Mol. Pharmaceutics, 7, 16671691 (2010).
27
Amorphous Dispersions

• A dispersion that greatly improves the
  dissolution of tenoxicam in water (via a high
  degree of supersaturation)
• Contains four discrete components

tenoxicam (singly ionized)
L-arginine (singly ionized)
L-arginine (zwitterionized)
Polyvinylpyrrolidine
Solid amorphous solution
J. Pharm. Sci. 2012, 101, 641-663.
28
Nanocrystallline dispersion
Polymer
Crystalline Domains 50 nm
Pharm. Res. 2012, 29, 1866-1881
29
Concluding Thoughts

• Multitude of options to characterize API and drug
  product material
• Relaxation methodology very powerful
• Expanding into 2D offers significant structure
  information