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[email protected] Lecture 1: Preformulation and Biopharmaceutical Considerations in Drug Product Design and Development
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Lecture 6: Biopharmaceutic Considerations
Lecture 2: Drug Substance Physical Form Selection
Lecture 7: Chemical Stability Assessment in Preformulation
Lecture 3: Drug Substance Physical Form Characterization
Lecture 8: Excipient Compatibility Studies
Lecture 4: Solubility: General Principles and Practical Considerations
Lecture 9: Impact of Material Properties on Formulation Development
Lecture 5: Dissolution and its Role in Solid Oral Dosage Form Development
Lecture 10: Prototype Formulations Screening and Characterization
NEW eCourse Available NOW! Visit www.aaps.org/PF101 for more information.
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Join the ACS Division of Medicinal Chemistry Today!
For $25 ($10 for students), You Will Receive: • A free copy of our annual medicinal chemistry review volume (over 600 pages, $160 retail price) • Abstracts of MEDI programming at national meetings • Access to student travel grants and fellowships Find out more about the ACS MEDI Division! www.acsmedchem.org
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Join us September 24, 2015 for the 9th Session!
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www.acs.org/content/acs/en/events/upcoming-acs-webinars/drug-design-2015.html
“2015 Drug Design and Delivery Symposium: Choices and Trends in Solid Dosage Form Selection”
Rao Mantri Bristol-Myers Squibb
Scott Trzaska J-Star Research
Ronald Smith Merck
Slides available now! Recordings will be available to ACS members after one week
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The 2015 Drug Design and Delivery Symposium is co-produced by the ACS Medicinal Chemistry Division and the AAPS
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Choices and Trends in Solid Dosage Form Selection: Salt, Cocrystal, Prodrug or Amorphous?
Scott Trzaska, J-Star Research
Ron Smith, Merck
August 27, 2015
Pharmaceutical Materials Particle Attributes O
API
OH
Solid State Form
O
O
Drug Product
Formulated Intermediate 16
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Form, Attributes, and Formulation
Solid State Form
Formulation
Stability Robust Crystallization Solubility
Enteric Coating Dispersions Solutions
Particle Attributes Filtration rates Content Uniformity Dissolution rate
Bioperformance
Manufacturability
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Solid State Forms • Polymorphs • Hydrates and solvates • Salts
+
• Cocrystals • Amorphous ++
++
-
-
-
-
-
+ + + +
-
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Prodrug
“Prodrugs in Drug Discovery” Thursday, November 19, 2015
John Higgins, Senior Principal Scientist, Discovery Pharmaceutical Sciences at Merck 19
The Ideal Solid State Form • Good biological performance • Suitable solid-state properties • Acceptable chemical and physical stability
• Manufacturing ease • Minimal risk 20
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Considerations • Phase of the program
• Indication • Dose • Formulation • Long term strategy 21
Solid State Form Selection Screen for crystalline candidates
Identify thermodynamic relationships Biological, physical, chemical, and mechanical properties Scale up Selection 22
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Solid State Form Selection Screen for crystalline candidates
Identify thermodynamic relationships Biological, physical, chemical, and mechanical properties Scale up
Selection 23
Screening Tools
Vapor Diffusion
Melt Crystallizations
Automated Crystallizations
Isothermal Crystallizations Sonication Induced Nucleation Variable Temperature Solvent Drop Grinding
Controlled Heating and Cooling
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Screening Techniques • Solution temperature cycling
• Slurry conversions
• Evaporative crystallizations
• Solid state temperature cycling
• Solvent vapor diffusion into solids • Antisolvent addition to solutions • Laser induced crystallization
• Mechanical activation
• Sublimation
• pH swings
Newman, A. Organic Process Research and Development 2013, 17 (3), 457 - 471, Specialized Solid Form Screening Techniques Lee, E. H. Asian Journal of Pharmaceutical Sciences 2014, 9 (4), 163 - 175, A Practical Guide to Pharmaceutical Polymorph Screening & Selection
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Solid State Form Selection Screen for crystalline candidates
Identify thermodynamic relationships Biological, physical, chemical, and mechanical properties Scale up Selection 26
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Thermodynamic Relationships • Temperature, pressure, and water activity • Polymorphs o Most stable o Transition temperatures
• Solvates and hydrates o Temperatures o Activities
• Salts • Cocrystals • Amorphous systems 27
Thermodynamics: Polymorphs • Monotropic • Enantiotropic • Transition temperature • Techniques oSolubility oSlurry transformations oCalorimetry
Miller, M. J.; Collman, B. M.; Greene, L. R.; Grant, D. J. W.; Blackburn, A. C. Pharmaceutical Development and Technology 2005, 10, 291 – 297, Identifying the Stable Polymorph Early in the Drug Discovery – Development Process Yu, L. Journal of Pharmaceutical Sciences 1995, 84, 966 – 974, Inferring Thermodynamic Stability Relationship of Polymorphs from Melting Data
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Most Stable Form: Solubility Form 3 Form 1
Form 2
Solubility
DG Form 1 Form 2 = RT ln (X2 /X1) DG Form 2 Form 3 = RT ln (X3 /X2) Ttransition
T
Form 2 is always more stable than Form 1, monotropic
Form 3 is more stable than Form 2 below Ttransition, enantiotropic
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Most Stable Form: Slurries • Diverse solvent systems o Functional groups, polarity, hydrogen bonding, activity
• Vary temperature • Days to weeks Form 1 [10 mg/mL]
Form 2 [5 mg/mL]
Solution
Form 1
Form 1
Form 1+2
Solvate
Form 2
Form 2
Gu, C.; Li, H.; Gandhi, R. B.; Raghavan, K. International Journal of Pharmaceutics 2004, 283, 117 – 125, Grouping Solvents by Statistical Analysis of Solvent Property Parameters: Implications to Polymorph Screening
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Thermodynamics: Hydrates • Understand relationship of anhydrous form and hydrate • Temperature • Pressure
• Water activity
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Anhydrous Versus Hydrate • Chemical potential impacts relative stability • mw = mw° + RT ln aw aw = gwXw mw = mw° + RT ln (gwXw) • Hydrate favored at high mw – T
– aw (Xw)
• Anhydrous form favored at low mw – T – aw (Xw)
• Anhydrous form is stable above critical T and below critical aw
+ 32
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Literature Example: Amgen • Originally isolating an anhydrous form • A hemihydrate was discovered during development
aw > 0.452, 25 °C
Anhydrous
Hemihydrate aw < 0.452, 25 °C
Morrison, H.; Quan, B. P.; Walker, S. D.; Hansen, K. B.; Nagapudi, K.; Cui, S. Organic Process Research and Development ASAP Article, DOI: 10.1021/acs.oprd.5b00030, Appearance of a New Hydrated Form during Development: A Case Study in Process and Solid-State Optimization
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Thermodynamics: Salts • Disproportionation • pH max • Excipients
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Solid-Solution Equilibria
B = Weak Base Ka
BH+Cl- = High Solubility
Solubility (mg/mL)
0
2
B + H+ + Cl-
Ssalt
S0
BH+Cl- (s)
4
S0 pHmax pKa log Ssalt
6
B = Low Solubility
BH+ + Cl-
B (s) 8
pH
10
12
14
pHmax
Serajuddin, A. T. M. Advanced Drug Delivery Reviews 2007, 59, 603 - 616, Salt Formation to Improve Drug Solubility
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Thermodynamics: Cocrystals • Ternary Phase diagram Solvent
API Cocrystal
Cocrystal Former 36
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Thermodynamics: Cocrystals • Ternary Phase diagram Solvent
API Cocrystal
Cocrystal Former 37
Thermodynamics: Amorphous • Dispersion – phase separation • Crystallization risk
• Humidity
Meng, F.; Dave, V.; Chauhan, H. European Journal of Pharmaceutical Sciences 2015, 77, 106 - 111, Qualitative and Quantitative Methods to Determine Miscibility in Amorphous Drug-Polymer Systems
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Solid State Form Selection Screen for crystalline candidates
Identify thermodynamic relationships Biological, physical, chemical, and mechanical properties Scale up
Selection 39
Properties Biological Performance • Solubility • Dissolution Rate • Particle Attributes • Excipients
Physical Stability • Thermodynamic stability • Risk of a form change • Processing space
Chemical Stability • Oxidation • Hydrolysis • Photochemical • Thermal decomposition
Mechanical Stability • Physical impact • Pressure • Disorder 40
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Solid State Form Selection Screen for crystalline candidates
Identify thermodynamic relationships Biological, physical, chemical, and mechanical properties Scale up
Selection 41
Scale Up • Thermodynamic or kinetic control? • Can the form be manufactured? o o o o
Crystallization Filtration Solvent removal Particle attribute control
• Can the form be formulated? 42
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Solid State Form Selection Screen for crystalline candidates
Identify thermodynamic relationships Biological, physical, chemical, and mechanical properties Scale up
Selection 43
Salts of Weak Acids and Bases: In Vivo Behavior Salts of acid 1-3
pH
4.5-6.8
• Can precipitate in the stomach in an uncontrolled fashion • May “parachute” in solution (supersaturation) • Free acid solubility increases with transit
Salts of base •
•
Stomach conditions favor the acid addition salts of bases Rate and extent of absorption depends on: o Dissolution in stomach o Precipitation vs absorption kinetics o Absorption window (site of absorption) 44
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Case Example: Ifetroban Sodium O- Na+
O O- Na +
O O N O O
O
O N
N N
O
• • • • •
Weak acid (pKa = 4.5) Solubility of sodium salt > 700 mg/mL Solubility of free acid = 0.007 mg/mL Conversion of Na salt to free acid in dosage form (micro-environmental pH) High solubility ration (salt to free form) not always desired
Serajuddin et. al., J. Pharm. Sci., 88(7), 696-704, 1999
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Case Example: Atazanavir Sulfate
4
Solubility (mg/mL)
3
S a l t
F r e e B a s e
2 p H a d j u s t e d w i t h H C l p H a d j u s t e d w i t h H 2 S O 4
• • •
1
• 0
0 1 2 3 4 5 6 7 8
•
p H
• US Patent: 6,087,383
Weak base (pKa = 4.7) Solubility
