– 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