Formulation 2

Global Technical Research & Development
FORMULATION DEVELOPMENT AND EVALUATION

Formulation Design
• Art, History, Trial and Error
– Modifications of Proven Formulations with NCE
– Typical Approaches for Solid Dosage Forms
– Decision Tree Logic
• Expert Systems
– Capsugel System
• Artifical Intelligence
– Decision Tree Logic with AI
– Multivariant Approaches

Formulation Design
• Definition of Dosage Form
• Definition of Product Composition
• Definition of Pharmaceutical Process
• Definition of In-Process Controls
• Definition of Product Specifications
• Definition of Product Packaging and Shipping


Formulation Design
Water Insoluble Injectable Compound
• Solubilization • Suspension
– pH adjustment – Suspension
– Surfactant – Nanosuspension
– Cosolvent – Emulsion
– Complexation – Microemulsion
– Lipid system
Formulation Design
Dry Blend Capsule Formulations
Ingredients Excipient Class Size 1 Capsule Size 0 Capsule

Percentage Composition
Drug 40 10
Lactose Filler/Diluent 74
Dibasic Calcium Filler/Diluent 53
Phosphate
Microcrystalline Filler/Diluent/ 15
Cellulose Wicking Agent
Crospovidone Disintegrant 4
Silicon Dioxide Glidant 1 0.25
Magnesium Lubricant 2 0.75
Stearate
Total Fill 300 340
Weight, mg

Formulation Design - Tablet Formulations
Ingredients Excipient Wet Wet Direct Direct
Class Gran. Gran. Comp. Comp.
Percentage Composition
Drug 67 67 21 5
Mannitol Filler/ 6 6
Diluent
Dibasic Calcium Filler/ 55
Phosphate Diluent
Microcrystalline Filler/ 20 10 20 37
Cellulose Diluent/
fine Wicking
Agent
Microcrystalline Filler/ 55
Cellulose Diluent/
coarse Wicking
Agent
Povidone Binder 2 2
Sodium Starch Disintegrant 4 2 2
Glycolate
Croscarmellose Disintegrant 2.5
Sodium
Microcrystalline Filler/ 10
Cellulose Diluent/
coarse Wicking
Agent
Sodium Starch Disintegrant 2
Glycolate
Silicon Dioxide Glidant 0.5
Magnesium Lubricant 1 1 1.5 0.5
Stearate
Total Core 450 450 480 200
Weight, mg

Roller Compaction Formulation Design DOE
In g re d ie n ts E x c ip ie n t R o lle r R o lle r R o lle r R o lle r W et
C la s s Com p. Com p. Com p. Com p. G ra n .
A B C D
DRUG 40 40 40 40 60
HPMC B in d e r 4
MCC F ille r/ 12 17 24 2 3 .2 5
DCP D ilu e n t 12 2 1 .5 1 6 .5 2 2 .7 5 2 7 .5
C ro s p o v id o n e D is in te g ra n t 2 3
C ro s c a rm e llo s e 3 4 5
S o d iu m
S ilic o n D io x id e G lid a n t 1 .5 1 .5 1 .5 1 .5 0 .5
SLS W e ttin g 1 2
P o lo x a m e r Agent 3 4 1
M a g n e s iu m L u b ric a n t 3 2
S te a ra te
H y d ro g e n a te d 3
C a s to r O il
S te a ric A c id 3
MCC F ille r/ 11
DCP D ilu e n t 12
C ro s p o v id o n e D is in te g ra n t 2 3
C ro s c a rm e llo s e 3 3
S o d iu m
S ilic o n D io x id e G lid a n t 1 .5 1 .5 1 .5 1 .5
SLS W e ttin g 1 2
P o lo x a m e r Agent 1 .5 1 .5
M a g n e s iu m L u b ric a n t 1
S te a ra te
H y d ro g e n a te d 1 1
C a s to r O il
S te a ric A c id 5
T o ta l C o re 500 500 500 500 350
W e ig h t, m g

Solubilization Strategies
Injectable Formulation
Yes pH Adjustment
Water-soluble?
Salt Formtion
No
Yes Cosolvents
Can a salt
be made? Yes Inclusion
START
Low Complexes
Suitable
Molecular
Shape?
No High
Nanosuspensions
Increasing drug polarity
Log P Dose No
High
High Low Cosolvents
Melting Micellar Dispersions
Point Emulsions
Low
Other Lipid Systems
FORMULATION DEVELOPMENT & EVALUATION Taste Masking

Active Pharmaceutical Ingredient
High dose High dose

Water Sensitive Water sensitive
Low dose Low dose
Water insoluble Large particles Water soluble
High dose
Yes No
Dry granulation
Alcohol Water Solution

Suspension Layering
layering Wet Granulation
Fluid Bed Coating with conventional polymers
Taste masked active particles


Formulation Design
Model Expert System

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


DOSAGE FORM EVALUATION
• In-Vitro
– Physical/Chemical Stability
– Processing
– Dissolution (Discriminating, Biorelevant, IVIVC)
• In-Vivo
– Pharmacokinetics

In-Vitro Evaluation
Granule Properties
(3% Binder Level)
Comparing Granulations using Kollidon 30 and Kollicoat IR
50.00
40.00
3% Kollidon 30
30.00
20.00 3% Kollicoat IR
10.00
% Weight Retained
0.00
20 40 80 120 200 325 Fines
Screen Size

In-Vitro Evaluation - Homogenization
After precipitation
Raw material After homogenization
Before homogenization
• Carbamazepine raw material


MA Copolymer Controlled Release
In-Vitro Dissolution - Method Development, pH Effects
Properties
100
80 pH = 1.5
1
2
60 3
4
5
40
%Theophylline Released
20
0
0 100 200 300 400 500 600 700 800
Time, min

MA Copolymer Controlled Release
In-Vitro Dissolution - Method Development, pH Effects
Properties
100
80
60
1
40 2
3
pH = 7.0
4
%Theophylline Released
20
5
0
0 100 200 300 400 500 600 700 800
Time, min

In-Vitro Dissolution
Capsules (50mg) dissolution at pH 6.8+0.1% SLS

120 n=2
20% dog capsules
100
80
CSF capsules
60 30% ME capsule 1
30% ME capsule 2
% Dissolved
20% ME capsule 1
30% dog capsules CSF capsule 1
40 CSF capsule 2
20% ME capsule 2
20
0
0 10 20 30 40 50 60
Time (min)

Dissolution Stability
40 Dissolution of 20% melt extrusion (pH2, non-sink) after 1 month storage

n=3
35
30
25
20
1 month 25C/60%RH closed
% Dissolved
15 1 month40C/75%RH closed
Initial analysis of dog capsules
End analysis of dog capsules (1 month ambient)
10
0
0 10 20 30 40 50 60
Time (min)

In-Vivo Evaluation
IDD-P™ Piroxicam IDD-P™ Flurbiprofen

100
1.0
0.8
Human Plasma 10 Flurbiprofen

0.6 Solution (high
5% Dextrose pH)
0.4 1 IDD-P™
Released Fraction
Flurbiprofen
Conc. (µg/mL in plasma)

0.2
0
0.0 0 2 4 6 8 10
0 20 40 60
Time (hours)
Time (min)
• High pH solution and IDDTM formulation display identical

IV-PK profile
GW Pace et al.; Pharm. Tech. (March 1999) MA Clement et al.;The Pharmacologist 34(3), 204 (1992)

In-Vitro Evaluation
Compression Profile
Compression Force Vs Ejection Force
200
150 Kollidon 30
100 Kollicoat IR
50
Ejection Force (N)

0
0 10 20 30
Compression Force (kN)

In-Vitro Evaluation
Compression Profile - Hardness
Compression Force Vs Hardness
20
15 Kollidon 30
Kollicoat IR
10
Hardness (Kp)
5
0
0 5 10 15 20 25 30
Compression Force (kN)

In-Vitro XRPD
No difference in crystal structure before and after homogenization

Formulation Evaluation in Dogs
80
70 Control
60 Formulation #2a
Formulation #2b
50
Formulation #2c
40
(ng/ml)
30
20
10
Mean Plasma Concentration

0
0 1 2 3 4 5 6 7 8
Time (hours)

100
Control
80 Formulation 1
Formulation 2
60 Formulation 3
40
20
Plasma Concentration (ng/ml)

0
0 4 8 12 16 20 24
Time (hr)

250
Control
Formulation 1
200 Formulation 2
Formulation 3
150
100
Concentration (ng/mL)
50
0
0 1 2 3 4 5 6 7 8
Time in Hour(s)

OraVescent™ Fentanyl - Buccal 30 minutes
0.6
0.5 Actiq®
Non-effervescent
0.4 OraVescent Buccal
0.3
0.2
Plasma Conc. (ng/ml)

0.1
0
0 5 10 15 20 25 30
Time (min)

OraVescent™ Fentanyl - Sublingual vs. Buccal 12 hours
0.5
0.4 SL Control
BL OraVescent
SL OraVescent
0.3
0.2
0.1
Plasma Conc. (ng/ml)

0
0 1 2 3 4 5 6 7 8 9 10 11 12
Time (hr)

OraVescent™ Fentanyl - Buccal 12 hours
0.6
0.5 Actiq®
Non-effervescent
0.4 OraVescent Buccal
0.3
0.2
Plasm a Conc. (ng/m l)

0.1
0
0 2 4 6 8 10 12
Time (hr)

Animal Pharmacokinetics
Mean PK profiles (n=4)
1000 Form A
Form B
Form C
Form D
100
10
Drug concentrations in plasma

1
0
0 4 8 12
Time (h)

Estimated Oral Bioavailability by Cross Study Comparison
Formulation Estimated Absolute Oral Bioavailability (% ± SD)
Control 7.6 ± 4.7
Formulation #1 19.9 ± 8.8**
Formulation #2 35.3 ± 10.6
Formulation #3 27.8 ± 21.7


Pharmacodynamics
• Dantrolene – skeletal muscle relaxant administered during anesthesia
• Very low volume and rapid IV administration possible
80
Intravenous injection of IDD-P™ Dantrolene
70
60
IDD-P™ Dantrolene rapidly lowers body temperature
50
40
Chemically induced hyperthermia
30
Temperature as indicated by
expired carbon dioxide (tor)
10 20 30 40 50 60
Time (min)
Karan et al.; Anesthesiology 79(3A), 437 (1993)


Inhalation Delivery Systems
• pressurized Metered Dose Inhaler (pMDI)
• Dry-powder inhaler (DPI)
• Nebulizer

pMDI
Advantages Disadvantages
• Portable • Patient coordination problems (i.e.
• Apparently Easy to Use/convenient press and breathe)
• Remaining Product Is Uncontaminated • Cold Freon effect
• Tamper-proof • High oropharyngeal deposition
• Protects Drug from Light, O2 and H2O • No dose counter
• Multiple Dose • Phase-out of CFCs
• Accurate Dose Metering • Complex patent situation
• High Respirable Fraction • lower dose limitation cf DPIs
• Inexpensive
• Mature Technology / Established
Vendors (> 40years)
Dry Powder Inhalers
• Convenient portable devices • Flow rate dependent performance
• Dose counter on most • Moisture protection required
• Easy to use • More expensive than pMDIs
• No propellants • Can be awkward to load
• Breath activated (no coordination • Not suitable infants
problems) –
• Higher drug payloads
–
Nebulizers
• No coordination required • Long treatment times, Heating
• Dosing using normal tidal • Bulky, inconvenient and complex to use
breathing • Expensive to manufacture
• All age groups • Erratic performance (variability)
• Acute care • High drug wastage (poor efficiency)
• Prone to microbiological contamination
• Poorly regulated, nebulizer is sold
independently of drug solution
DPI - Formulations
•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
DPI - Formulations
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
• 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
Delivery From DPI

upon inhalation Redispersion of primary
Drug/Carrier Blend drug particles

pMDI Formulations
• Surfactant • Active Substance (DS)
- lecithin, sorbitan trioleate, oleic - suspended or in solution
acid depending on solubility in p-
- aids wetting of DS during blend mixture (salt forms)
manufacture - particle size reduction by
- stabilization of drug particles micronization (90%< 5µm,
against coagulation and/or rapid 0%>10µm)
flocculation - chemical stability in p-mixture
- aid solubilization of DS for solution - physical stability in p-mixture
formulations (polymorphic changes, solvate
formation, crystal growth from
- valve lubrication/functionality Ostwald ripening)
• Co-solvent
- ethanol to solubilize surfactants
- reduce vapour pressure

pMDI Container Closure Systems
• Container
Aluminium alloy, coatings (stability) or glass
• Valve
Available in different metering volumes (25, 50, 63 and
100µl), suppliers and components mechanical
stability over shelf life
• Actuator
Available range, colors, shapes and sizes
Extension of valve stem
Geometry affect characteristics of aerosol plume
FORMULATION DEVELOPMENT AND EVALUATION - pMDI

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Global Technical Research & Development

FORMULATION DEVELOPMENT AND EVALUATION

FORMULATION DEVELOPMENT AND EVALUATION

• Definition of Dosage Form

• Definition of Product Composition

• Definition of Pharmaceutical Process

• Definition of In-Process Controls

• Definition of Product Specifications

• Definition of Product Packaging and Shipping

FORMULATION DEVELOPMENT AND EVALUATION

Water Insoluble Injectable Compound

Ingredients Excipient Class Size 1 Capsule Size 0 Capsule

FORMULATION DEVELOPMENT AND EVALUATION

FORMULATION DEVELOPMENT AND EVALUATION

FORMULATION DEVELOPMENT AND EVALUATION

FORMULATION DEVELOPMENT & EVALUATION Taste Masking

High dose High dose

Alcohol Water Solution

Fluid Bed Coating with conventional polymers

Taste masked active particles

FORMULATION DEVELOPMENT AND EVALUATION

Model Expert System

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

FORMULATION DEVELOPMENT AND EVALUATION

FORMULATION DEVELOPMENT AND EVALUATION

Comparing Granulations using Kollidon 30 and Kollicoat IR

FORMULATION DEVELOPMENT AND EVALUATION

• Carbamazepine raw material

FORMULATION DEVELOPMENT AND EVALUATION

FORMULATION DEVELOPMENT AND EVALUATION

FORMULATION DEVELOPMENT AND EVALUATION

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

FORMULATION DEVELOPMENT AND EVALUATION

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

FORMULATION DEVELOPMENT AND EVALUATION

IDD-P™ Piroxicam IDD-P™ Flurbiprofen

Human Plasma 10 Flurbiprofen

Conc. (µg/mL in plasma)

• High pH solution and IDDTM formulation display identical

FORMULATION DEVELOPMENT AND EVALUATION

Compression Force Vs Ejection Force

Ejection Force (N)

FORMULATION DEVELOPMENT AND EVALUATION

Compression Profile - Hardness

Compression Force Vs Hardness

FORMULATION DEVELOPMENT AND EVALUATION

FORMULATION DEVELOPMENT AND EVALUATION

Mean Plasma Concentration

FORMULATION DEVELOPMENT AND EVALUATION

Plasma Concentration (ng/ml)

FORMULATION DEVELOPMENT AND EVALUATION

FORMULATION DEVELOPMENT AND EVALUATION

Plasma Conc. (ng/ml)

FORMULATION DEVELOPMENT AND EVALUATION

Plasma Conc. (ng/ml)

FORMULATION DEVELOPMENT AND EVALUATION

Plasm a Conc. (ng/m l)

FORMULATION DEVELOPMENT AND EVALUATION

Drug concentrations in plasma

FORMULATION DEVELOPMENT AND EVALUATION

Formulation Estimated Absolute Oral Bioavailability (% ± SD)

Control 7.6 ± 4.7

Formulation #1 19.9 ± 8.8**