expediting time-to-market and reducing time-to-launch with physicochemical optimization

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

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

Outline





3

Overall Considerations in Selecting the Correct Form

4

Solid State Bio-pharmaceutics Stability Mechanical

Properties

Formulation Design &Product Design

(Dosage Form Design)

Process Design

Workflow for Merck Strategy

5

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

Only a Short Time to Select the Form in Year 1

Matest Major Focus of SSC

Form Selection

Form Selection

Polymorphs Salts Cocrystals Amorphous forms Nanoparticles (crystalline or amorphous)

8

Screening Strategy - 1995

9

Development Strategy with Polymorph Screening – 8 Weeks

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SolubilityStudy

Is drugsoluble?

Week 1 Week 4 Week 5 Week 8

SolubilityDissolution

Salt Screen

Polymorph Screen SelectForm Rat PKFormulation

Screen

Stress Testing

Can itform salts?

Yes

No

SolubilityDissolution

SelectForm Rat PKFormulation

Screen

Stress TestingMilling Study

Salt PolymorphScreen

SelectForm

Amorphous Dispersion Screen SelectForm

SolubilityDissolution Rat PK

Stress TestingCrystallization

Inhibitor Screen

Optional

Optional

Yes

No

Vehicle Screen SelectVeh.

SolubilityDissolution Rat PK

Stress Testing

Development Strategy First 4 weeks

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SolubilityStudy

Is drugsoluble?

Week 1 Week 4

Salt Screen

Polymorph Screen

Can itform salts?

Yes

No

SelectForm

Amorphous Dispersion Screen

Yes

No

Vehicle Screen

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

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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

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Levitation Equipment

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Levitation Equipment on Beamline 11-ID-C

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Each drop contains about 0.1 mg of drug (assuming solubility = 10 mg/mL)

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-ra

y in

tens

ity (a

bs. c

ount

s)

Q (A-1)

4-Bromoacetanilid

-2000

-1000

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

0 2 4 6 8

x-ra

y in

tens

ity (a

bs. c

ount

s)Q (A-1)

ItraconazoleKetoconazoleRitonavirefavirenz

Fast Crystallizers

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Slow Crystallizers

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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

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Salt Properties

compound meltingpoint (ºC)

percent weightgain at 81% RH

aqueous solubility(mg/mL)

aqueous dissolution rateat pH3 (mg/min/cm2)

naproxen 160 0 0.016 ≤0.005Na salt 267 21 178 21

THAM salt 191 0 11 1.0

H3CO

CO2

CH3

H3N

OH

OHHO

NSAID

Gu, L.; Strickley, R. G. Pharmaceutical Research 1987, 4, 255

Three Tier Salt Selection - Morris

Tier 1 Hygroscopicity (7 Salts)

Tier 2 Solubility Crystal Changes

(4 salts)

Tier 3 Stability and Compatibility

DSC Curves for the Calcium Salt of BMS 180431

5%RH

70%RH

Powder XRD Patterns of the Magnesium Salt of BMS 180431

Equilibrium Solubilities of BMS 180431 Salts in Water and 0.01M HCl

Salts Distilled WaterSolubility**

(mg/mL)

0.01M HClSolubility*(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

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

Outline





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

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Three Tier Salt Selection

Tier 1 Hygroscopicity (7 Salts)

Tier 2 Solubility Crystal Changes

(4 salts)

Tier 3 Stability and Compatibility

DSC Curves for the Calcium Salt of BMS 180431

5%RH

70%RH

Powder XRD Patterns of the Magnesium Salt of BMS 180431

Equilibrium Solubilities of BMS 180431 Salts in Water and 0.01M HCl

Salts Distilled WaterSolubility**

(mg/mL)

0.01M HClSolubility*(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

Outline





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33 33

Solid Dispersion – Spring and Parachute Concept

J. Brouwers, Brewster et al J Pharm Sci (2009) 98: 2549-2572

34 34

Supersaturated Dissolution

cLogP Tg Tm

Friesen, D.T. et al Mol Pharm 5 (2008) 1003-1019

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In vivo Exposure

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

Outline





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Itraconazole Blood Levels in Pigs

01020304050607080

00.

5 1 2 4 8 12 16 2431

.3 36 42 48

Conc

entr

atio

n itr

acon

azol

e (n

g/m

l)

Time (h)

average sporanox

average itra 100mg

average Itra HPMC 300mg

average itra HPMCP

Dissolution Rates – An IVIVC

ITR Dispersions with Controls

Dissolution - USP I (Basket)Media (0.1N HCl, 0.5%CTAB), 50rpm(1hr), 250rpm

0

10

20

30

40

50

60

70

80

90

100

0 500 1000 1500 2000 2500 3000

Time (min)

% D

rug

Rel

ease

Sporanox 100mg

ITR HPMCP55(1:2) 300mg

ITR HPMC(1:2) 300mg

ITR Crystalline 100mg

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

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Improved Pharma Services

Chemical synthesis Solid state chemistry Preclinical/Toxicology IND Clinical Trials

Stability & Consistency Quality by design Validated methods Regulatory issues Intellectual Property

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.

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Four Examples of Claims

Conclusion





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expediting time-to-market and reducing time-to-launch with physicochemical optimization

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