Decreasing Time-to-Market via Synchrotron Utilization to Discover Stable Formulation from Steve Byrn & Pam Smith at Purdue University / Improved Pharma. This presentation focuses on finding solid forms to increase exposure, synchotron, amorphous complexes, predict/anticipate stability and synchotron / sameness and problem solving. Pam and Steve delivered this talk at the 2018 Controlled & Modified Drug Release Summit.

1. Pamela A. Smith, Ph.D.
pam@leadingsmartscience.com
(765)412-2677
1
Decreasing Time-to-Market
via Synchrotron Utilization
to Discover Stable
Formulation
Focus on Finding a Solid Form that
will Increase Exposure

2. Outline
2

3. Outline
 Decrease time to market
⚫ fIND
⚫ Synchrotron
⚫ Amorphous complexes
 Predict/anticipate stability
⚫ Synchrotron
 Sameness and problem solving
⚫ Synchrotron
3

4. DECREASE TIME TO MARKET
4

5. 5
Expensive, long, risky, highly regulated
8-10 years development
Billion dollar development cost for a new drug
Classical New Drug R&D

6. 6
Chorus Timeframe & Costs
⚫ Timeframe (Chorus)
• Ind. Av.: 42 mo.
• Chorus: 30 mo.
⚫ Costs (Chorus)
• Ind. Av.: $30M
• Chorus: $3M

7. Byrn/Chen EAS2018 7
New Business Model
➢ Accelerating Proof-of-Concept Study
Phase I and Phase IIa
➢ Make amorphous complexes of most candidates for
accelerated toxicology and early animal studies
➢ Faster turnaround, more opportunities

8. 8
fIND Strategy – Improved Pharma

9. SYNCHROTRON
9

10. The Advanced Photon Source
10

11. 11
Synchrotron high energy x-ray experiment

12. Resources
 Advanced Photon Source (Argonne)
⚫ Chris Benmore
 National Synchrotron Light Source
(Brookhaven)
⚫ Simon Billinge
 Swiss Light Source (Paul Scherrer
Institute)
⚫ Excelsus Structural Solutions
12

13. GO DIRECTLY TO COMPLEXES
13

14. Amorphous Complex Strategy
14

15. 15
Lapatinib –
HPMCP Salt
Complex

16. Solid SEDDS-like
Formulation
 Drug
 Alcohol
 Non-ionic surfactant
 Triglyceride
 Example - Ritonavir
16

17. Ritonavir + surfactants +
polymers
17
I. Tho et al. / European Journal of Pharmaceutical Sciences 40 (2010) 25–32
Only the
complexes give
a nano-
suspension

18. Amorphous Complexes
18
Log in Samples
Make
Complexes
Stability
1 Week
X-ray Argonne
PDF
Diff. PDF
PDF
Action
Spray-dry Evaporation
X-ray Argonne
PDF
Diff. PDF
Scale up

19. Design Complexes
 Utilize structural knowledge of drug
and excipients
 Utilize literature on solid SEDDs
formulations
 Utilize literature on hydrogen bonding
 Utilize solution NMR to test
association and chemical shift
changes
19

20. SYNCHROTRON
20

21. PDF Structure Analysis – Domains
in Drug Amorphous Preparations
21
Arrows
Represent
Nearest
Neighbor
(NN) and
NNN and
NNNN
Contacts
Benmore, Byrn, et a., Journal of Pharmaceutical Sciences (2013), 102(4), 1290-1300.

22. Neighbors in Amorphous
Systems
22
NNN
NN
NNNN

23. Need to Work at a
Synchrotron for PDF
23

24. Lapatinib PDF – Left HPMC, Right
HPMCP - Differential PDFs are Shown
24
Pure LP
3:1
1:1
1:3
Pure LP
3:1
1:1
1:3
This is the only dispersion
lacking domains

25. N-15 SSNMR of Lapatinib with
HPMCP
25

26. SYNCHROTRON “LAB ON A
DROP” TO SAVE MATERIAL
26

27. Levitation Equipment
27

28. Amorphous Screen Using
Levitated Drops
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http://www.youtube.com/watch?v=669AcEBpdsY

29. Levitation Equipment on Beamline 11-
ID-C
29
Each drop contains about 0.1 mg of drug
(assuming solubility = 10 mg/mL)

30. Fast Evaporation in Levitator
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Complete evaporation takes about 16 min

31. X-ray Patterns from Levitation
Experiments
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-2000
0
2000
4000
6000
8000
10000
12000
14000
0 2 4 6 8
x-rayintensity(abs.counts)
Q (A-1)
4-Bromoacetanilid
-2000
-1000
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
0 2 4 6 8
x-rayintensity(abs.counts) Q (A-1)
Itraconazole
Ketoconazole
Ritonavir
efavirenz

32. Acoustic Levitation – A First Step
in Finding the Right Formulation
 Avoids need for large quantities of API
required in standard amorphous screens
 Avoids crystallization induced by containers
 Is much faster than standard screens
 Allows detection of domains in amorphous
screens – predicts stability
 Simulates spray-drying
 Finds the best formulation
32

33. PREDICT/ANTICIPATE
STABILITY
33

34. Lapatinib PDF – Left HPMC, Right
HPMCP - Differential PDFs are Shown
34
Pure LP
3:1
1:1
1:3
Pure LP
3:1
1:1
1:3
This is the only stable dispersion –
a lapatinib-HPMC salt complex

35. SAMENESS OF CLINICAL
SUPPLIES AND PROBLEM
SOLVING
35

36. Sameness Analysis
36

37. Sameness Study - Noise
37

38. Conclusion
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