Choices and Trends in Solid Dosage Form Selection€œPaving Your Eligibility Pathway: Green Card...

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NEW eCourse Available NOW! Visit www.aaps.org/PF101 for more information.

Lecture 1: Preformulation and Biopharmaceutical

Considerations in Drug Product Design and

Development

Lecture 2: Drug Substance Physical Form Selection

Lecture 3: Drug Substance Physical Form

Characterization

Lecture 4: Solubility: General Principles and Practical

Considerations

Lecture 5: Dissolution and its Role in Solid Oral

Dosage Form Development

Lecture 6: Biopharmaceutic Considerations

Lecture 7: Chemical Stability Assessment in

Preformulation

Lecture 8: Excipient Compatibility Studies

Lecture 9: Impact of Material Properties on

Formulation Development

Lecture 10: Prototype Formulations

Screening and Characterization

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The 2015 Drug Design and Delivery Symposium is co-produced by the ACS Medicinal Chemistry Division and the AAPS

“2015 Drug Design and Delivery Symposium: Choices and Trends in Solid Dosage Form Selection”

Ronald Smith Merck

Rao Mantri Bristol-Myers Squibb

Scott Trzaska J-Star Research

8/27/2015

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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

16

O OH

O

O

API Solid State Form

Particle Attributes

Formulated Intermediate

Drug Product

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17 Manufacturability Bioperformance

Solid State Form Stability

Robust Crystallization Solubility

Formulation Enteric Coating

Dispersions Solutions

Particle Attributes Filtration rates

Content Uniformity Dissolution rate

Form, Attributes, and Formulation

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• Polymorphs

• Hydrates and solvates

• Salts

• Cocrystals

• Amorphous

-

-

-

-

+

+ +

+

-

-

-

-

+

+ +

+

+

Solid State Forms

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“Prodrugs in Drug Discovery”

Thursday, November 19, 2015

John Higgins, Senior Principal Scientist,

Discovery Pharmaceutical Sciences at Merck

Prodrug

19

The Ideal Solid State Form

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• Good biological performance

• Suitable solid-state properties

• Acceptable chemical and physical stability

• Manufacturing ease

• Minimal risk

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• Phase of the program

• Indication

• Dose

• Formulation

• Long term strategy

Considerations

21

Solid State Form Selection

22

Biological, physical, chemical,

and mechanical properties

Identify thermodynamic relationships

Screen for crystalline candidates

Scale up

Selection

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Scale up

Selection

Screening Tools

24

Melt

Crystallizations

Vapor

Diffusion

Controlled Heating

and Cooling Sonication Induced

Nucleation Variable Temperature

Solvent Drop Grinding

Isothermal

Crystallizations

Automated

Crystallizations

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• Solution temperature cycling

• Evaporative crystallizations

• Solvent vapor diffusion into solids

• Laser induced crystallization

• Sublimation

• Slurry conversions

• Solid state temperature cycling

• Antisolvent addition to solutions

• Mechanical activation

• pH swings

25

Screening Techniques

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


26




Scale up

Selection


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• Temperature, pressure, and water activity

• Polymorphs o Most stable

o Transition temperatures

• Solvates and hydrates o Temperatures

o Activities

• Salts

• Cocrystals

• Amorphous systems

Thermodynamic Relationships

27

• Monotropic

• Enantiotropic

• Transition temperature

• Techniques oSolubility

oSlurry transformations

oCalorimetry

Thermodynamics: Polymorphs

28

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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Ttransition

Most Stable Form: Solubility

29

Solubility

T

Form 1 Form 2

Form 2 is always more stable than Form 1, monotropic

DG Form 1 Form 2 = RT ln (X2 /X1)

Form 3

Form 3 is more stable than Form 2 below Ttransition, enantiotropic

DG Form 2 Form 3 = RT ln (X3 /X2)

Most Stable Form: Slurries

30 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

Form 1

Form 1 Form 1 + 2

Solvate Form 2 Form 2

Form 1

[10 mg/mL]

Form 2

[5 mg/mL] Solution

• Diverse solvent systems

o Functional groups, polarity, hydrogen bonding, activity

• Vary temperature

• Days to weeks

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Thermodynamics: Hydrates

31

• Understand relationship of anhydrous form and hydrate

• Temperature

• Pressure

• Water activity

Anhydrous Versus Hydrate

32

+

• 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

8/27/2015

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• Originally isolating an anhydrous form

• A hemihydrate was discovered during development

Literature Example: Amgen

33

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

Anhydrous Hemihydrate

aw > 0.452,

25 °C

aw < 0.452,

25 °C

Thermodynamics: Salts

34

• Disproportionation

• pH max

• Excipients

8/27/2015

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Solid-Solution Equilibria

35

0 2 4 6 8 10 12 14

Solu

bility

(mg/m

L)

pH

BH+Cl- (s)

BH+ + Cl-

Ssalt

B + H+ + Cl-

B (s)

S0

B = Weak Base

BH

+C

l- =

Hig

h S

olu

bili

ty

B =

Low

Solu

bility

Ka

pHmax

Serajuddin, A. T. M. Advanced Drug Delivery Reviews 2007, 59, 603 - 616, Salt Formation to Improve Drug Solubility

salt

0amax

S

S log pK pH

Thermodynamics: Cocrystals

36

• Ternary Phase diagram Solvent

API Cocrystal

Former Cocrystal

8/27/2015

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Thermodynamics: Cocrystals

37

• Ternary Phase diagram Solvent

API Cocrystal

Former Cocrystal

Thermodynamics: Amorphous

38

• 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

8/27/2015

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39



Scale up

Selection



Biological Performance

• Solubility

• Dissolution Rate

• Particle Attributes

• Excipients

Physical Stability

• Thermodynamic stability

• Risk of a form change

• Processing space

40

Properties

Chemical Stability

• Oxidation

• Hydrolysis

• Photochemical

• Thermal decomposition

Mechanical Stability

• Physical impact

• Pressure

• Disorder

8/27/2015

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41





Selection

Scale up

• Thermodynamic or kinetic control?

• Can the form be manufactured? o Crystallization

o Filtration

o Solvent removal

o Particle attribute control

• Can the form be formulated?

Scale Up

42

8/27/2015

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43





Scale up

Selection

Salts of Weak Acids and Bases: In Vivo Behavior

Salts of acid • 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)

pH

1-3

4.5-6.8

44

8/27/2015

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Case Example: Ifetroban Sodium

O

N

O

N

O

O-

Na+

O

O

N

O

N

O

O-

Na+

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 45

Case Example: Atazanavir Sulfate

pH

012345678

Solubility

(mg/mL)

0

1

2

3

4

pH adjusted with HCl

pH adjusted with H2SO4

Salt Free Base• Weak base (pKa = 4.7)

• Solubility <0.001 mg/ml (above pH 4.2)

• Bisulfate salt dissolves to a higher extent than its equilibrium value

• The higher initial solubility, though temporary, helps in its dissolution- absorption behavior

• Free base gave ~0% oral bioavailability; Bisulfate salt exhibited ~ 20% absolute oral bioavailability in dogs

• Bisulfate salt selected as final form US Patent: 6,087,383 46

8/27/2015

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Role of Form, Formulation and Dose on Oral Fraction Absorbed

Dose Number Absorption Number Dissolution Number

Oh et al, Pharm. Res., 10, 264-70, 1993

Dose & Solubility Permeability Particle Size

Key Parameters

47

Phase Selection Attributes: When does particle size influence oral absorption?

Dissolution-limited absorption

• Dissolution rate slower than permeability

• Reduction in particle size translates to improved oral bioavailability

Permeability-limited absorption

• Permeability slower than dissolution rate

• No effect of particle size reduction (micronization) on oral bioavailability

Solubility-limited absorption

• When dose is very high relative to solubility

• No effect of particle size reduction (micronization) on oral bioavailability

• Many drugs are dissolution-limited at low doses and solubility-limited at high doses

Biopharmaceutics Classification Scheme

48

8/27/2015

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Increasing Oral Exposure: Particle size reduction or amorphous?

49 Fakes et al, Int. J. Pharm., 370:167-174, 2009

Summary

50





Scale up

Selection

8/27/2015

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51 Manufacturability Bioperformance

Solid State Form Stability

Robust Crystallization Solubility

Formulation Enteric Coating

Dispersions Solutions

Particle Attributes Filtration rates

Content Uniformity Dissolution rate

Form, Attributes, and Formulation

52




Ronald Smith Merck



8/27/2015

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www.acs.org/content/acs/en/events/upcoming-acs-webinars/drug-design-2015.html 53

Join us September 24, 2015

for the 9th Session!

Upcoming ACS Webinars www.acs.org/acswebinars

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®



“How to Create a Safer and More Sustainable Lab

Through Green Chemistry”

Jeffrey Whitford, Director of Global Citizenship, Sigma-Aldrich

David C. Finster, Professor of Chemistry, Wittenberg University


“Paving Your Eligibility Pathway: Green Card Tips for

Scientists, Professors and Researchers”

Peter F. Asaad, Managing Partner, Immigration Solutions Group, PLLC

Meredith Jolie, Attorney, Immigration Solutions Group, PLLC

8/27/2015

28

55




Ronald Smith Merck



• Neuroinflammation

• Cancer Immunotherapy

• Heart Failure

• Natural Products

• Protein-Protein Interactions

• Drug Safety

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Featured Topics:

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NEW eCourse Available NOW! Visit www.aaps.org/PF101 for more information.

Lecture 1: Preformulation and Biopharmaceutical

Considerations in Drug Product Design and

Development

Lecture 2: Drug Substance Physical Form Selection

Lecture 3: Drug Substance Physical Form

Characterization

Lecture 4: Solubility: General Principles and Practical

Considerations

Lecture 5: Dissolution and its Role in Solid Oral

Dosage Form Development

Lecture 6: Biopharmaceutic Considerations

Lecture 7: Chemical Stability Assessment in

Preformulation

Lecture 8: Excipient Compatibility Studies

Lecture 9: Impact of Material Properties on

Formulation Development

Lecture 10: Prototype Formulations

Screening and Characterization

Be a featured fan on an upcoming webinar! Write to us @ [email protected]

58

How has ACS Webinars benefited you?

®

“As a pharmacologist, ACS Webinars have

provided me with a better understanding of the

chemistry aspects of my projects and enabled

me to interact effectively with my chemist

collaborators.”

Abir El-Alfy, Ph.D.

Associate Professor, Pharmaceutical Sciences

College of Pharmacy, Chicago State University

http://www.aaps.org/PF101

8/27/2015

30

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youtube.com/acswebinars

Search for “acswebinars” and connect!

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NEW! Free Access to ACS Presentations on Demand® ACS Member only access to over 1,000 presentation recordings from recent ACS meetings and select events.

NEW! ACS Career Navigator Your source for leadership development, professional education, career services, and much more.

8/27/2015

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Choices and Trends in Solid Dosage Form Selection€œPaving Your Eligibility Pathway: Green Card...

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