FORMULATION DEVELOPMENT AND EVALUATION

– Decision Tree Logic with AI – Multivariant Approaches • Artifical Intelligence – Capsugel System • Expert Systems – Modifications of Proven Form...
Author: Marion Flynn
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– Decision Tree Logic with AI – Multivariant Approaches

• Artifical Intelligence

– Capsugel System

• Expert Systems

– Modifications of Proven Formulations with NCE – Typical Approaches for Solid Dosage Forms – Decision Tree Logic

• Art, History, Trial and Error

FORMULATION DEVELOPMENT AND EVALUATION Formulation Design

Global Technical Research & Development

• Definition of Product Packaging and Shipping

• Definition of Product Specifications

• Definition of In-Process Controls

• Definition of Pharmaceutical Process

• Definition of Product Composition

• Definition of Dosage Form

FORMULATION DEVELOPMENT AND EVALUATION Formulation Design

Global Technical Research & Development

– – – – –

pH adjustment Surfactant Cosolvent Complexation Lipid system

• Solubilization – – – –

Suspension Nanosuspension Emulsion Microemulsion

• Suspension

Water Insoluble Injectable Compound

FORMULATION DEVELOPMENT AND EVALUATION Formulation Design

Global Technical Research & Development

Drug Lactose Dibasic Calcium Phosphate Microcrystalline Cellulose Crospovidone Silicon Dioxide Magnesium Stearate Total Fill Weight, mg

Ingredients

Filler/Diluent/ Wicking Agent Disintegrant Glidant Lubricant

Filler/Diluent Filler/Diluent

Excipient Class

0.25 0.75 340

4 1 2 300

15

Size 1 Capsule Size 0 Capsule Percentage Composition 40 10 74 53

FORMULATION DEVELOPMENT AND EVALUATION Formulation Design Dry Blend Capsule Formulations

Global Technical Research & Development

Sodium Starch Glycolate Silicon Dioxide Magnesium Stearate Total Core Weight, mg

Povidone Sodium Starch Glycolate Croscarmellose Sodium Microcrystalline Cellulose coarse

Microcrystalline Cellulose coarse

Dibasic Calcium Phosphate Microcrystalline Cellulose fine

Drug Mannitol

Ingredients

1 450

1 450

Glidant Lubricant

10

2 2

10

2

2 4

20

480

0.5 1.5

2

55

20

200

0.5

2.5

37

55

Wet Wet Direct Direct Gran. Gran. Comp. Comp. Percentage Composition 67 67 21 5 6 6

Filler/ Diluent/ Wicking Agent Disintegrant

Disintegrant

Filler/ Diluent Filler/ Diluent Filler/ Diluent/ Wicking Agent Filler/ Diluent/ Wicking Agent Binder Disintegrant

Excipient Class

FORMULATION DEVELOPMENT AND EVALUATION Formulation Design - Tablet Formulations

Global Technical Research & Development

M a g n e s iu m S te a ra te H y d ro g e n a te d C a s to r O il S te a ric A c id T o ta l C o re W e ig h t, m g

M a g n e s iu m S te a ra te H y d ro g e n a te d C a s to r O il S te a ric A c id MCC DCP C ro s p o v id o n e C ro s c a rm e llo s e S o d iu m S ilic o n D io x id e SLS P o lo x a m e r

C ro s p o v id o n e C ro s c a rm e llo s e S o d iu m S ilic o n D io x id e SLS P o lo x a m e r

DRUG HPMC MCC DCP

In g re d ie n ts

1 .5 1

G lid a n t W e ttin g Agent

500

1

1 .5 1

G lid a n t W e ttin g Agent L u b ric a n t

11 12 2

F ille r/ D ilu e n t D is in te g ra n t

3

2

D is in te g ra n t

L u b ric a n t

12 12

R o lle r Com p. A 40

B in d e r F ille r/ D ilu e n t

E x c ip ie n t C la s s

5 500

1 .5

1 .5

500

1

1 .5

3

1 .5

3

3

4

3 3

1 .5

4

24 1 6 .5

R o lle r Com p. C 40

1 .5

3

17 2 1 .5

R o lle r Com p. B 40

500

1

1 .5 2

3

1 .5 2

3

2 3 .2 5 2 2 .7 5

R o lle r Com p. D 40

350

2

1

0 .5

5

2 7 .5

60 4

W et G ra n .

FORMULATION DEVELOPMENT AND EVALUATION Roller Compaction Formulation Design DOE

Global Technical Research & Development

START

No

Can a salt be made?

Yes

Low

Log P

High

No

Water-soluble?

Melting Point

High

Yes

Low

Low

Dose

High

No

Suitable Molecular Shape?

Yes

Cosolvents Micellar Dispersions Emulsions Other Lipid Systems

Nanosuspensions

Inclusion Complexes

Cosolvents

pH Adjustment Salt Formtion

Injectable Formulation

FORMULATION DEVELOPMENT AND EVALUATION Solubilization Strategies

Global Technical Research & Development

Increasing drug polarity

Suspension layering

No

Alcohol Water Wet Granulation

Yes

Large particles High dose Dry granulation

High dose Water sensitive

Solution Layering

Low dose Water soluble

Taste masked active particles

Fluid Bed Coating with conventional polymers

Low dose Water insoluble

High dose Water Sensitive

FORMULATION DEVELOPMENT & EVALUATION Taste Masking Active Pharmaceutical Ingredient

Global Technical Research & Development

Guo, M., et. al.,Pharm. Tech., 26(9), 2002, p. 44 - 60

CAPEX

Model Expert System

FORMULATION DEVELOPMENT AND EVALUATION Formulation Design

Global Technical Research & Development

– Pharmacokinetics

• In-Vivo

– Physical/Chemical Stability – Processing – Dissolution (Discriminating, Biorelevant, IVIVC)

• In-Vitro

FORMULATION DEVELOPMENT AND EVALUATION DOSAGE FORM EVALUATION

Global Technical Research & Development

% Weight Retained

0.00

10.00

20.00

30.00

40.00

50.00

20

40

80

Screen Size

120

200

325

Fines

3% Kollicoat IR

3% Kollidon 30

Comparing Granulations using Kollidon 30 and Kollicoat IR

(3% Binder Level)

Granule Properties

FORMULATION DEVELOPMENT AND EVALUATION In-Vitro Evaluation

Global Technical Research & Development



After precipitation Before homogenization

Carbamazepine raw material

Raw material

After homogenization

FORMULATION DEVELOPMENT AND EVALUATION In-Vitro Evaluation - Homogenization

Global Technical Research & Development

Global Technical Research & Development

0

20

40

60

80

100

0

100

1 2 3 4 5

200

Properties

300

400 500 Time, min

pH = 1.5

600

700

800

FORMULATION DEVELOPMENT AND EVALUATION MA Copolymer Controlled Release In-Vitro Dissolution - Method Development, pH Effects

%Theophylline Released

Global Technical Research & Development

0

20

40

60

80

100

0

100

200

Properties

300

400 Time, min

500

pH = 7.0

600

700

1 2 3 4 5

800

FORMULATION DEVELOPMENT AND EVALUATION MA Copolymer Controlled Release In-Vitro Dissolution - Method Development, pH Effects

%Theophylline Released

0

20

40

60

80

100

120

0

10

20

Time (min)

30

CSF capsules

30% dog capsules

20% dog capsules

40

50

60

30% ME capsule 1 30% ME capsule 2 20% ME capsule 1 CSF capsule 1 CSF capsule 2 20% ME capsule 2

Capsules (50mg) dissolution at pH 6.8+0.1% SLS n=2

FORMULATION DEVELOPMENT AND EVALUATION In-Vitro Dissolution

Global Technical Research & Development

% Dissolved

Global Technical Research & Development

0

5

10

15

20

25

30

35

40

0

10

20

Time (min)

30

40

50

1 month 25C/60%RH closed 1 month40C/75%RH closed Initial analysis of dog capsules End analysis of dog capsules (1 month ambient)

Dissolution of 20% melt extrusion (pH2, non-sink) after 1 month storage n=3

FORMULATION DEVELOPMENT AND EVALUATION Dissolution Stability

% Dissolved

60

Released Fraction

0.0

0.2

0.4

0.6

0.8

1.0

Time (min)

20

40

60

GW Pace et al.; Pharm. Tech. (March 1999)

0

5% Dextrose

Human Plasma

IDD-P™ Piroxicam



0

2

6

Time (hours)

4

8

10

IDD-P™ Flurbiprofen

Flurbiprofen Solution (high pH)

MA Clement et al.;The Pharmacologist 34(3), 204 (1992)

High pH solution and IDDTM formulation display identical IV-PK profile

0

1

10

100

IDD-P™ Flurbiprofen

FORMULATION DEVELOPMENT AND EVALUATION In-Vivo Evaluation

Global Technical Research & Development

Conc. (µg/mL in plasma)

Global Technical Research & Development

0

50

100

150

200

0

20

Compression Force (kN)

10

Compression Force Vs Ejection Force

Compression Profile

30

Kollicoat IR

Kollidon 30

FORMULATION DEVELOPMENT AND EVALUATION In-Vitro Evaluation

Ejection Force (N)

Global Technical Research & Development

0

5

10

15

20

0

5

15

20

Compression Force (kN)

10

25

Compression Force Vs Hardness

Compression Profile - Hardness

30

Kollicoat IR

Kollidon 30

FORMULATION DEVELOPMENT AND EVALUATION In-Vitro Evaluation

Hardness (Kp)

No difference in crystal structure before and after homogenization

In-Vitro XRPD

FORMULATION DEVELOPMENT AND EVALUATION

Global Technical Research & Development

Global Technical Research & Development

0

10

20

30

40

0

1

2

3

4 Time (hours)

5

6

7

Formulation #2c

Formulation #2b

Formulation #2a

60

50

Control

70

80

FORMULATION DEVELOPMENT AND EVALUATION Formulation Evaluation in Dogs

Mean Plasma Concentration (ng/ml)

8

Plasma Concentration (ng/ml)

0

20

40

60

80

100

0

4

8

12 Time (hr)

16

20

Formulation 3

Formulation 2

Formulation 1

Control

FORMULATION DEVELOPMENT AND EVALUATION Formulation Evaluation in Dogs

Global Technical Research & Development

24

Concentration (ng/mL)

0

50

100

150

200

250

0

1

2

3

Time in Hour(s)

4

5

6

7

Control Formulation 1 Formulation 2 Formulation 3

FORMULATION DEVELOPMENT AND EVALUATION Formulation Evaluation in Dogs

Global Technical Research & Development

8

Global Technical Research & Development

0

0.1

0.2

0.3

0.4

0.5

0.6

0

5

10

15 Time (min)

Actiq® Non-effervescent OraVescent Buccal

20

25

FORMULATION DEVELOPMENT AND EVALUATION OraVescent™ Fentanyl - Buccal 30 minutes

Plasma Conc. (ng/ml)

30

Global Technical Research & Development

0

0.1

0.2

0.3

0.4

0.5

0

1

2

3

4

5

Time (hr)

6

7

8

9

10

SL Control BL OraVescent SL OraVescent

11

FORMULATION DEVELOPMENT AND EVALUATION OraVescent™ Fentanyl - Sublingual vs. Buccal 12 hours

Plasma Conc. (ng/ml)

12

0

0.1

0.2

0.3

0.4

0.5

0.6

0

2

4

Time (hr)

6

8

10

Actiq® Non-effervescent OraVescent Buccal

FORMULATION DEVELOPMENT AND EVALUATION OraVescent™ Fentanyl - Buccal 12 hours

Global Technical Research & Development

Plasm a Conc. (ng/m l)

12

0

1

10

100

1000

0

4 Time (h)

Mean PK profiles (n=4)

8

Form D

Form C

Form B

Form A

12

FORMULATION DEVELOPMENT AND EVALUATION Animal Pharmacokinetics

Global Technical Research & Development

Drug concentrations in plasma

Estimated Absolute Oral Bioavailability (% ± SD)

7.6 ± 4.7

19.9 ± 8.8**

35.3 ± 10.6

27.8 ± 21.7

Formulation

Control

Formulation #1

Formulation #2

Formulation #3

FORMULATION DEVELOPMENT AND EVALUATION Estimated Oral Bioavailability by Cross Study Comparison

Global Technical Research & Development

10

30

Time (min)

20

Chemically induced hyperthermia

40

50

60

IDD-P™ Dantrolene rapidly lowers body temperature

Intravenous injection of IDD-P™ Dantrolene

Karan et al.; Anesthesiology 79(3A), 437 (1993)

30

40

50

60

70

80

Dantrolene – skeletal muscle relaxant administered during anesthesia Very low volume and rapid IV administration possible

Temperature as indicated by

• •

FORMULATION DEVELOPMENT AND EVALUATION Pharmacodynamics

Global Technical Research & Development

expired carbon dioxide (tor)

pressurized Metered Dose Inhaler (pMDI)

Dry-powder inhaler (DPI)

Nebulizer







FORMULATION DEVELOPMENT AND EVALUATION Inhalation Delivery Systems

Global Technical Research & Development

• • • • • •

Patient coordination problems (i.e. press and breathe) Cold Freon effect High oropharyngeal deposition No dose counter Phase-out of CFCs Complex patent situation lower dose limitation cf DPIs



• • • • • • • • • •

Portable Apparently Easy to Use/convenient Remaining Product Is Uncontaminated Tamper-proof Protects Drug from Light, O2 and H2O Multiple Dose Accurate Dose Metering High Respirable Fraction Inexpensive Mature Technology / Established Vendors (> 40years)

Disadvantages

Advantages

FORMULATION DEVELOPMENT AND EVALUATION pMDI

Global Technical Research & Development





Flow rate dependent performance Moisture protection required More expensive than pMDIs Can be awkward to load Not suitable infants

• • • • •

• • • • •

Convenient portable devices Dose counter on most Easy to use No propellants Breath activated (no coordination problems) • Higher drug payloads

Disadvantages

Advantages

FORMULATION DEVELOPMENT AND EVALUATION Dry Powder Inhalers

Global Technical Research & Development

• • • • • • •

• No coordination required • Dosing using normal tidal breathing • All age groups • Acute care

Long treatment times, Heating Bulky, inconvenient and complex to use Expensive to manufacture Erratic performance (variability) High drug wastage (poor efficiency) Prone to microbiological contamination Poorly regulated, nebulizer is sold independently of drug solution

Disadvantages

Advantages

FORMULATION DEVELOPMENT AND EVALUATION Nebulizers

Global Technical Research & Development

•Adhesive forces between drug and carrier particles should also be sufficient to prevent segregation during transport and storage • Carrier factors that affect DPI efficiency: Particle size distribution, surface, charge • Drug substance factors that affect DPI efficiency: Particle size, surface, shape, charge, hygroscopicity, drug/carrier ratio, crystallinity, physical stability of crystalline/amorphous form • Other formulation approaches for DPIs Crystal engineering of DS using supercritical fluids Use of ternary components Spray drying processes for sensitive biomolecules

FORMULATION DEVELOPMENT AND EVALUATION DPI - Formulations

Global Technical Research & Development

Drug/Carrier Blend

Delivery From DPI upon inhalation

Redispersion of primary drug particles

• Adhesive forces between drug and carrier particles are the most critical parameter that determines the degree of redispersion of micronized primary particles in the inspired air stream

Majority of DPI formulations comprise of micronized drug mixed with an inert carrier (usually lactose) as a bulking agent, to aid processability and manufacturing (flowablity filling into devices/packaging materials) and to enhance fluidisability during inhalation

FORMULATION DEVELOPMENT AND EVALUATION DPI - Formulations

Global Technical Research & Development

• Surfactant - lecithin, sorbitan trioleate, oleic acid - aids wetting of DS during blend manufacture - stabilization of drug particles against coagulation and/or rapid flocculation - aid solubilization of DS for solution formulations - valve lubrication/functionality • Co-solvent - ethanol to solubilize surfactants - reduce vapour pressure

• Active Substance (DS) - suspended or in solution depending on solubility in pmixture (salt forms) - particle size reduction by micronization (90%< 5µm, 0%>10µm) - chemical stability in p-mixture - physical stability in p-mixture (polymorphic changes, solvate formation, crystal growth from Ostwald ripening)

FORMULATION DEVELOPMENT AND EVALUATION pMDI Formulations

Global Technical Research & Development

Available range, colors, shapes and sizes Extension of valve stem Geometry affect characteristics of aerosol plume

• Actuator

Available in different metering volumes (25, 50, 63 and 100µl), suppliers and components mechanical stability over shelf life

• Valve

Aluminium alloy, coatings (stability) or glass

• Container

FORMULATION DEVELOPMENT AND EVALUATION pMDI Container Closure Systems

Global Technical Research & Development

FORMULATION DEVELOPMENT AND EVALUATION - pMDI

Global Technical Research & Development

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