Expediting Time-to-Market and Reducing Time-to-Launch with Physicochemical Optimization - Stephen R. Byrn - Purdue University

1. Expediting Time-to-Market and
Reducing Time-to-Launch with
Physicochemical Optimization
Stephen R. Byrn
Purdue University and Improved Pharma, LLC
West Lafayette, Indiana
1

2. Outline
 Effectively selecting the correct form and correct salt of
your drug substance
 Examining key strategies for managing solubility in lead
optimization
 Evaluating physicochemical properties, generating an
understanding of the material’s stability under various
conditions, leading to selecting the optimal drug delivery
system
 Achieving the right balance between efficacy,
patentability concerns, toxicity, and ADME properties for
your compound
2

3. Outline
 Effectively selecting the correct form and correct salt of
your drug substance
 Examining key strategies for managing solubility in lead
optimization
 Evaluating physicochemical properties, generating an
understanding of the material’s stability under various
conditions, leading to selecting the optimal drug delivery
system
 Achieving the right balance between efficacy,
patentability concerns, toxicity, and ADME properties for
your compound
3

4. Overall Considerations in Selecting the
Correct Form
Bio- Mechanical
Solid State Stability
pharmaceutics Properties
Formulation Design &
Product Design
(Dosage Form Design)
Process Design
4

5. Workflow for Merck Strategy
Michael Palucki, John D. Higgins, Elizabeth Kwong, and
Allen C. Templeton, J. Med. Chem., 53, 5897 (2010)
5

6. Only a Short Time to Select the Form in
Year 1
Major Focus
Matest
of SSC

7. Form Selection

8. Form Selection
 Polymorphs
 Salts
 Cocrystals
 Amorphous forms
 Nanoparticles (crystalline or amorphous)
8

9. Screening Strategy - 1995
9

10. Development Strategy with Polymorph Screening
– 8 Weeks
Week 1 Week 4 Week 5 Week 8
Solubility Is drug Yes Select Formulation Solubility
Study soluble? Polymorph Screen Form Screen Dissolution
Rat PK
No
Stress Testing
Can it Yes Select Salt Polymorph Select Formulation Solubility
form salts? Salt Screen Form Screen Form Screen Dissolution
Rat PK
Optional
Stress Testing
No Milling Study
Select Solubility
Amorphous Dispersion Screen Form Dissolution
Rat PK
Optional
Stress Testing
Crystallization
Inhibitor Screen
Select Solubility
Vehicle Screen Veh. Dissolution
Rat PK
Stress Testing
10

11. Development Strategy First 4 weeks
Week 1 Week 4
Solubility Is drug Yes
Study soluble? Polymorph Screen
No
Can it Yes Select
form salts? Salt Screen Form
No
Amorphous Dispersion Screen
Vehicle Screen
11

12. Strategy
 Optimize form and formulation early
 Merck Review in J. Med. Chem. Present similar strategy – see Higgins et al., Michael Palucki, John D.
Higgins, Elizabeth Kwong, and Allen C. Templeton, J. Med. Chem., 53, 5897 (2010)
 Find best form within 12 weeks for toxicology
and first in human clinical trials
 Utilize acoustic levitation method to facilitate
early formulation development
12

13. Acoustic Levitation – A Frist Step in
Finding the Right Form
 Finding best form
 Very small amounts of material
 One day study
 Can apply Taylor method to determine if the
compound is a fast crystallizer
 Simulates spray drying
13

14. Levitation Equipment
14

15. Levitation Equipment on Beamline 11-ID-C
Each drop contains about 0.1 mg of drug
(assuming solubility = 10 mg/mL) 15

16. X-ray Patterns from Levitation Experiments
9000
14000
8000
12000
x-ray intensity (abs. counts)
7000 Itraconazole
x-ray intensity (abs. counts)
10000 6000
Ketoconazole
4-Bromoacetanilid
Ritonavir
8000 5000
efavirenz
4000
6000
3000
4000
2000
2000
1000
0 0
0 2 4 6 8 0 2 4 6 8
-2000 -1000
Q (A-1)
-2000
Q (A-1)
16

17. Fast Crystallizers
17

18. Slow Crystallizers
18

19. Nanoparticles
 Screen for nanoparticles in the case of fast
crystallization
 Wet mill stable polymorph
 Utilize Liversidge screen for crystal growth
inhibitors – US Patent 5,145,684
19

20. Salt Properties
CH3 OH
CO2 H3N
OH
H3CO HO
NSAID
compound melting percent weight aqueous solubility aqueous dissolution rate
point (ºC) gain at 81% RH (mg/mL) at pH3 (mg/min/cm2)
naproxen 160 0 0.016 ≤0.005
Na salt 267 21 178 21
THAM salt 191 0 11 1.0
Gu, L.; Strickley, R. G. Pharmaceutical Research 1987, 4, 255

21. Three Tier Salt Selection - Morris
Tier 1 Hygroscopicity
(7 Salts)
Tier 2 Solubility Crystal Changes
(4 salts)
Tier 3 Stability and Compatibility

22. DSC Curves for the
Calcium Salt of BMS 180431
5%RH
70%RH

23. Powder XRD Patterns of the
Magnesium Salt of BMS 180431

24. Equilibrium Solubilities of BMS
180431 Salts in Water and 0.01M HCl
Salts Distilled Water 0.01M HCl
Solubility** Solubility*
(mg/mL) (mg/mL)
Calcium 2.8 0.67
Magnesium 3.7 0.65
Lysine >100 0.64
Arginine >100 0.61
* 25°C; µ = 0.1
** Solubilities are expressed in terms of free acid concentration

25. Solid State Accelerated Stability Testing
Results of the Arginine and Lysine Salts

26. Outline
 Effectively selecting the correct form and correct salt of
your drug substance
 Examining key strategies for managing solubility in lead
optimization
 Evaluating physicochemical properties, generating an
understanding of the material’s stability under various
conditions, leading to selecting the optimal drug delivery
system
 Achieving the right balance between efficacy,
patentability concerns, toxicity, and ADME properties for
your compound
26

27. Dissolution Studies of Formulations (50 mg
drug formulation in capsule)- in situ probe
27

28. Three Tier Salt Selection
Tier 1 Hygroscopicity
(7 Salts)
Tier 2 Solubility Crystal Changes
(4 salts)
Tier 3 Stability and Compatibility

29. DSC Curves for the
Calcium Salt of BMS 180431
5%RH
70%RH

30. Powder XRD Patterns of the
Magnesium Salt of BMS 180431

31. Equilibrium Solubilities of BMS
180431 Salts in Water and 0.01M HCl
Salts Distilled Water 0.01M HCl
Solubility** Solubility*
(mg/mL) (mg/mL)
Calcium 2.8 0.67
Magnesium 3.7 0.65
Lysine >100 0.64
Arginine >100 0.61
* 25°C; µ = 0.1
** Solubilities are expressed in terms of free acid concentration

32. Outline
 Effectively selecting the correct form and correct salt of
your drug substance
 Examining key strategies for managing solubility in lead
optimization
 Evaluating physicochemical properties, generating an
understanding of the material’s stability under various
conditions, leading to selecting the optimal drug delivery
system
 Achieving the right balance between efficacy,
patentability concerns, toxicity, and ADME properties for
your compound
32

33. Solid Dispersion – Spring and
Parachute Concept
J. Brouwers, Brewster et
al J Pharm Sci (2009)
98: 2549-2572
33
33

34. Supersaturated Dissolution
Friesen, D.T. et al
Mol Pharm
5 (2008) 1003-1019
cLogP Tg Tm
34
34

35. In vivo Exposure
Beagle Dog, 5 x increase in exposure
Friesen, D.T. et al
Mol Pharm
35 5 (2008) 1003-1019

36. Outline
 Effectively selecting the correct form and correct salt of
your drug substance
 Examining key strategies for managing solubility in lead
optimization
 Evaluating physicochemical properties, generating an
understanding of the material’s stability under various
conditions, leading to selecting the optimal drug delivery
system
 Achieving the right balance between efficacy,
patentability concerns, toxicity, and ADME properties for
your compound
36

37. Itraconazole Blood Levels in Pigs
80
Concentration itraconazole (ng/ml)
70
60 average sporanox
50
40 average itra 100mg
30
20 average Itra HPMC
10 300mg
0
average itra HPMCP
12
16
24
36
42
48
31.3
0
1
2
4
8
0.5
Time (h)

38. Dissolution Rates – An IVIVC
ITR Dispersions with Controls
Dissolution - USP I (Basket)
100 Media (0.1N HCl, 0.5%CTAB), 50rpm(1hr), 250rpm
90
80
70
% Drug Release
60
50
40
30
Sporanox 100mg
20 ITR HPMCP55(1:2) 300mg
10 ITR HPMC(1:2) 300mg
ITR Crystalline 100mg
0
0 500 1000 1500 2000 2500 3000
Time (min)

39. Improved Pharma Strategy for Fast
Development – 1 Year to IND
 Improved Pharma is a Virtual Company
 CRO Strategy – IP Belongs to Contractor
 Merck approach
 Michael Palucki, John D. Higgins, Elizabeth Kwong, and Allen C. Templeton, J. Med. Chem., 53, 5897 (2010)
 Best in Class, US Subcontractors/Performance Sites
 Argonne National Labs
 SSCI, an Aptuit Company
 Purdue University
 A specific strategy, flow chart, timeline and plan
developed for each compound
39

40. Improved Pharma Services
 Chemical synthesis  Stability & Consistency
 Solid state chemistry  Quality by design
 Preclinical/Toxicology  Validated methods
 IND  Regulatory issues
 Clinical Trials  Intellectual Property

41. Intellectual Property
 Include best method of making cocrystals-
salts-polymorphs (amorphous forms)-
nanocrystals
 Patent form and formulation
 Be sure to have claims that describe your
invention is various ways and with various
degrees of specificity.
41

42. Four Examples of Claims

43. Conclusion
 Effectively selecting the correct form and correct salt
of your drug substance
 Examining key strategies for managing solubility in
lead optimization
 Evaluating physicochemical properties, generating
an understanding of the material’s stability under
various conditions, leading to selecting the optimal
drug delivery system
 Achieving the right balance between efficacy,
patentability concerns, toxicity, and ADME
properties for your compound
43