Formulation Development & Evaluation - Novartis

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 Design
pH adjustment
Surfactant
Cosolvent
Complexation
Lipid system
Solubilization
Suspension
Nanosuspension
Emulsion
Microemulsion
Suspension
Water Insoluble Injectable Compound

Formulation Design
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 Design
Dry Blend Capsule Formulations
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
4
20
480
0.5
1.5
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 Design - Tablet Formulations
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 .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
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 .5
1 .5
3
3
1 .5
24
1 6 .5
R o lle r
Com p.
C
40
1 .5
17
2 1 .5
R o lle r
Com p.
B
40
500
1 .5
2
1 .5
2
2 3 .2 5
2 2 .7 5
R o lle r
Com p.
D
40
350
0 .5
2 7 .5
60
4
W et
G ra n .

Roller Compaction Formulation Design DOE
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

Solubilization Strategies
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
Guo, M., et. al.,Pharm. Tech., 26(9), 2002, p. 44 - 60
CAPEX
Model Expert System

Formulation Design
Pharmacokinetics
In-Vivo
Physical/Chemical Stability
Processing
Dissolution (Discriminating, Biorelevant, IVIVC)
In-Vitro

DOSAGE FORM EVALUATION
% 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

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

In-Vitro Evaluation - Homogenization
20
40
60
80
100
100
1
2
3
4
5
200
Properties
300
400
500
Time, min
pH = 1.5
600
700
800

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

MA Copolymer Controlled Release
In-Vitro Dissolution - Method Development, pH Effects
%Theophylline Released
20
40
60
80
100
120
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

In-Vitro Dissolution
% Dissolved
10
15
20
25
30
35
40
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

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)
5% Dextrose
Human Plasma
IDD-P Piroxicam
Time (hours)
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
10
100
IDD-P Flurbiprofen

In-Vivo Evaluation
Conc. (g/mL in plasma)
50
100
150
200
20
Compression Force (kN)
10
Compression Force Vs Ejection Force
Compression Profile
30
Kollicoat IR
Kollidon 30

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

In-Vitro Evaluation
Hardness (Kp)
No difference in crystal structure before and after homogenization
In-Vitro XRPD
10
20
30
40
4
Time (hours)
Formulation #2c
Formulation #2b
Formulation #2a
60
50
Control
70
80

Formulation Evaluation in Dogs
Mean Plasma Concentration

(ng/ml)
Plasma Concentration (ng/ml)
20
40
60
80
100
12
Time (hr)
16
20
Formulation 3
Formulation 2
Formulation 1
Control

24
Concentration (ng/mL)
50
100
150
200
250
Time in Hour(s)
Control
Formulation 1
Formulation 2
Formulation 3

0.1
0.2
0.3
0.4
0.5
0.6
10
15
Time (min)
Actiq
Non-effervescent
OraVescent Buccal
20
25

OraVescent Fentanyl - Buccal 30 minutes
Plasma Conc. (ng/ml)
30
0.1
0.2
0.3
0.4
0.5
Time (hr)
10
SL Control
BL OraVescent
SL OraVescent
11

OraVescent Fentanyl - Sublingual vs. Buccal 12 hours
Plasma Conc. (ng/ml)
12
0.1
0.2
0.3
0.4
0.5
0.6
Time (hr)
10
Actiq
Non-effervescent
OraVescent Buccal

OraVescent Fentanyl - Buccal 12 hours
Plasm a Conc. (ng/m l)
12
10
100
1000
4
Time (h)
Mean PK profiles (n=4)
Form D
Form C
Form B
Form A
12

Animal Pharmacokinetics
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

Estimated Oral Bioavailability by Cross Study Comparison
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

Pharmacodynamics
expired carbon dioxide (tor)
pressurized Metered Dose Inhaler (pMDI)
Dry-powder inhaler (DPI)
Nebulizer

Inhalation Delivery Systems
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

pMDI
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

Dry Powder Inhalers
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

Nebulizers
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
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

DPI - Formulations
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%< 5m,
0%>10m)
- chemical stability in p-mixture
- physical stability in p-mixture
(polymorphic changes, solvate
formation, crystal growth from
Ostwald ripening)

pMDI Formulations
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

100l), suppliers and components mechanical
stability over shelf life
Valve
Aluminium alloy, coatings (stability) or glass
Container

pMDI Container Closure Systems
FORMULATION DEVELOPMENT AND EVALUATION - pMDI

Formulation Development & Evaluation - Novartis

Загружено:

Сведения о документе

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Formulation Development & Evaluation - Novartis

Загружено:

Авторское право:

Доступные форматы

Decision Tree Logic with AI

Modifications of Proven Formulations with NCE

Art, History, Trial and Error

FORMULATION DEVELOPMENT AND EVALUATION

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

Global Technical Research & Development

Water Insoluble Injectable Compound

FORMULATION DEVELOPMENT AND EVALUATION

Global Technical Research & Development

FORMULATION DEVELOPMENT AND EVALUATION

Global Technical Research & Development

FORMULATION DEVELOPMENT AND EVALUATION

Global Technical Research & Development

FORMULATION DEVELOPMENT AND EVALUATION

Global Technical Research & Development

FORMULATION DEVELOPMENT AND EVALUATION

Global Technical Research & Development

Increasing drug polarity

Taste masked active particles

Fluid Bed Coating with conventional polymers

FORMULATION DEVELOPMENT & EVALUATION Taste Masking

Global Technical Research & Development

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

Model Expert System

FORMULATION DEVELOPMENT AND EVALUATION

Global Technical Research & Development

FORMULATION DEVELOPMENT AND EVALUATION

Global Technical Research & Development

Comparing Granulations using Kollidon 30 and Kollicoat IR

(3% Binder Level)

FORMULATION DEVELOPMENT AND EVALUATION

Global Technical Research & Development

Carbamazepine raw material

FORMULATION DEVELOPMENT AND EVALUATION

Global Technical Research & Development

Global Technical Research & Development

FORMULATION DEVELOPMENT AND EVALUATION

Global Technical Research & Development

FORMULATION DEVELOPMENT AND EVALUATION

30% dog capsules

20% dog capsules

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

FORMULATION DEVELOPMENT AND EVALUATION

Global Technical Research & Development

Global Technical Research & Development

1 month 25C/60%RH closed

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

FORMULATION DEVELOPMENT AND EVALUATION

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

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

High pH solution and IDDTM formulation display identical

FORMULATION DEVELOPMENT AND EVALUATION

Global Technical Research & Development

Conc. (g/mL in plasma)

Global Technical Research & Development

Compression Force (kN)