scale of science in pharmaceutical development
DESCRIPTION
Understanding the Pharmaceutical DevelopmentTRANSCRIPT
May 26, 2011 1
Scale of Science
Understanding of
Interactions and Controls in
Pharmaceutical Developmentwith reference to solid dosages
By
Satendra Kumar Vishwakarma, PhD
May 26, 2011 2
WelcomeThis Presentation is dedicated to inventor of
Lipinski’s “Rule-of-Five” in Drug Candidate
Screening Methodology
Dr Christopher A. LipinskiExploratory Medicinal Sciences Department
Laboratories of Pfizer Global Research & Development, Connecticut,
USA.
May 26, 2011 3
A n n o u n c e m e n t
The views and graphics in this presentation are collected from
various sources and content(s) might have been modified on
the basis of scientific justification.
Narrator of this slide presentation believes that all the contents are Up-to-Date and is
ONLY for INFORMATION, NOT for direct APPLICATION without verifying, optimizing,
and validating the target.
Thank You
May 26, 2011 4
Understanding the Scale of Science
A
Fundamental Tools
in
Pharmaceutical Development
May 26, 2011 5
Lab scale
Process
Development
Scale -up
for Mfg
Commercial
Pilot
Plant
Scale-up
Develop
GMP
Process
Expression
System
Selection
Cell Line Selection
Fermentation Dev
Purification
Process Dev
Process
Integration
Tech Xfer from
Development to
Pilot Plant
Pilot Plant
Readiness
Engineering
Trials for Tox
Lots
Consistency
Runs
MBR/SOP’s
Finalization
GMP
Production for
Ph1
Process
ModificationMBR/SOP’s
Modification
Develop
Commercial
Process
Analytical Method Development
Process
Optimization
Process
Validation
Bridging Studies
Preformulation Formulation
Fill/Finish
Stability Studies
Analytical SOP to QC
TOX/ADME
Early Process Development Activities
GLP “Tox” Lots GMP Ph1 – 2
Clinical Supplies
Ph 3 Clinical
Supplies
Transfer to
Manufacturing Site
Launch
Phillip L. Gomez III, NIH, USA
Science based compatibility & Stability Studies
May 26, 2011 6
Lipinski's Rule-of-Five Analysis
A significant empirical derivation from the analysis of World
Drug Index (32,000) facilitates to make the distinction
between Drug-Like and Non-Drug-Like molecule.
In order to be adsorbed through the gut and enter the blood
stream, orally administered drugs must have certain
molecular properties as proposed by Lipinski.
The Lipinski "Rule of Five Analysis" states that compounds
are likely to have good absorption and permeation in
biological systems (ADME) and are more likely to be
successful drug candidates if they meet the following criteria:
Christopher A. Lipinski Exploratory Medicinal Sciences Department, Connecticut, laboratories
of Pfizer Global Research & Development
May 26, 2011 7
Lipinski's Rule-of-Five Analysis
Five or fewer hydrogen-bond donors (any OH+NH).
Ten or fewer hydrogen-bond acceptors (any O+N).
Molecular weight less than or equal to 500.
Calculated log P less than or equal to 5.
Fifth rule includes Number of rotatable bonds LT 15,
and other factors – number of aromatic rings, highly reactive and chemically unstable groups.
Compound classes that are substrates for biological transporters are exceptions to the rule.
If two parameters are out of range, a "poor absorption or permeability is possible" alert is a very visible educational tool for the chemist and serves as a tracking tool for the research organization.
May 26, 2011 8
Lipinski's Rule-of-Five Analysis
hydrogen-bond donors
May 26, 2011 9
Lipinski's Rule-of-Five Analysis
hydrogen-bond acceptors
May 26, 2011 10
Lipinski's Rule-of-Five AnalysisThe compounds in Collection of Small Organic Molecules generally obey
Lipinski's "rule of five" making them ideal candidates for drug discovery.
Molecular weight
May 26, 2011 11
Lipinski's Rule-of-Five Analysis
Log P
May 26, 2011 12
Lipinski's Rule-of-Five Analysis
Number of rotatable bonds
May 26, 2011 13
Drug-Like vs Non Drug-Like
May 26, 2011 14
Drug-Like vs Non Drug-Like
May 26, 2011 15
Integrated Workflow Station
Accelerate solubility, salt form, polymorphic form
and crystallization to minimize potential risk of new
polymorphic form
Reduce time, resource and material by a factor of
10
Large combinatorial experiment specifications i.e.
pre-formulation variables, experiment execution,
end-to-end software and database integration, high
quality productivity, fast submission
May 26, 2011 16
Automated Workflow Station
http://www.symyx.com http://www.chemspeed.com
Pharmaceutical Workflows Overview
Design Synthesis, processing, formulation Sample preparation
for screening Properties analysis Data analysis
May 26, 2011 17
Automated Workflow StationSolubility Workflows Overview
http://www.symyx.com
Accelerating Innovation for Broad Range of Applications
Process Development Optimization: Automated Solubility v pH
Measurements Discovery: Solubility Measurements Formulation, pH, and
Stability Testing
May 26, 2011 18
Molecular Pre-Formulation
Scale of Science
GENERIC HPLC METHODS
Benefits of Fast Generic Chromatographic Methods over Traditional or Custom Chromatographic Methods
A knowledge of Molecule Structure and Retention
Time is relevant in Early- / Pre- Formulation
Development
May 26, 2011 19
HPLC in Pre-formulation DevelopmentWith a wide variety of analytical columns, detection systems, mobile phases, and
sample pre-treatment techniques, most physicochemical changes in formulation
components can be analyzed
HPLC Columns:
HPLC Detectors:
HPLC Analysis:
Quantitative analysis of physical degradation products
Quantitative analysis of chemical degradation products
Characterization of product impurities
Rapid identification and concentration determination of products
UV/VIS, Fluorescence, Reflective index, Mass spectrometers, Light scattering,
evaporative light scattering, Electrochemical, Chemiluminescence, Circular
Dichroism
Size-exclusion (or gel filtration), Reversed-phase, Ion-exchange, Hydrophobic
interaction, Affinity
May 26, 2011 20
Generic Gradient HPLC Methods
Characteristics of rapid, generic gradient methods
A combination of Methods – eliminate the need for method development.
Covers wide range of polarity range (Polar Ionic Mode, Reverse Phase, Polar Organic Mode, Normal Phase for MD).
Application of short columns with small particles (Column coupling for multi-column screening for MD).
Compromise resolution for speedy results (Quality is not so important for screening of physical parameters and MD).
Application of elevated column temp and high flow rate.
Rapid extraction of Physiochemical Parameters for quality drug
development and Generic Screening for Method Development
(MD)
May 26, 2011 21
DETECTOR
AUTOSAMPLER
PUMP
Configuration of MDS with Isocratic System
http://www.astecusa.com/publications/presentations/58.PPT#16
Generic Gradient HPLC Methods
May 26, 2011 22
Molecular Pre-Formulation
Scale of Science
UNDERSTANDING OF FUNDAMENTAL PHYSICOCHEMICAL
THEORY AND TECHNIQUES IN PREFORMULATION
Knowledge of Molecule Structure & Interactions is vital to
understand manufacturing science through Pre-Formulation
/ Formulation Development
May 26, 2011 23
Introductory Pre-formulation Chapters
Interface between formulation development and Early formulation in drug innovation.
Data on solubility determinations
Physical chemical characterization of solids (thermal methods, XRPD, particle size, moisture sorption).
Polymorph screening studies & relative stability determinations of detected solid phases.
Characterize API in formulated product to support pharmacology, toxicology, and PK.
May 26, 2011 24
Core Formulation
Functional
Activities
Method
Development
Optimization
Method
Validation
Transfer
In vitro
Release
Testing
Analytical Testing
Procedures
Specifications
Reference
Standard
Characterization
Reverse
Engineering
Vendor
Qualification
Stability
Evaluation
Dosage Development Groups
Early and
Preformulation
May 26, 2011 25
Drug
Characteristics
PC and Stability
Disintegration
of
FormulationDrug
Dissolution
Drug
Absorption
Drug
DistributionDrug
Metabolism
Drug
Excretion
Influencing Parameters
Bioequivalence____________________________________
Bioavailability
May 26, 2011 26
Dosage Form Development Chart
Active Drug
SuspensionSolution
Intrinsic
Dissolution
Dissociation
Constant pKa
Intrinsic
Solubility
Suppositories Topicals
pH Effect Co-solvents
Capsule
Salts Saturated
Solubility IV Injection
Solution
Other
Delivery
System
Other
Dosage Forms
Tablets
Stability
Tonic
Adjustment
Tonic
Adjustment
Excipient Compatibility
PEG 400 + 5%
H2O + Glycerin
pH?
May 26, 2011 27
Formulation Problem
May 26, 2011 28
Challenges in Development
Crystalline, Amorphous
Solvates / HydratesExcipient
Compatibility
Physical and
Chemical
Mechanical
Properties Plastic,
Elastic, Brittle
Solid State Stability
Physical and
Chemical
Degradation
Pathway Prediction &
Characterization
Solid State Properties
Particle size, Shape
Surface Area
Characterization
?
May 26, 2011 29
NEW CHEMICAL
ENTITY
Chemical Form(s)
Polymorphs
Hydrates
Solvates
Neutral compoundSalt Forms
SOLID STATE
PROPERTIES
Aqueous and pH Solubility
& Stability Particle Morphology
Mechanical Properties
ABSORPTION
CHARACTERISTICS
Challenges in Development
API Properties
Ionizable Group (s)
Physical Form (s)
Crystallinity
SOLUTION
CHARACTERISTICS
May 26, 2011 30
Excipient Selection in Dosages
Excipients Choice
in Solid Dosage
Forms
Physicochemical Properties
of Drug
Polymorphic / Forms
Hydrates
Heat & moisture
sensitive
Poorly Soluble
Poorly absorbable
Poorly Stable in vivo
Physicochemical
Properties of Excipient
Physically Stable
(Polymorphic / Forms
Hydrates)
Hygroscopic
Chemically Stable
Compatible with drug
Rheology Flow
Route of Administration
Oral
Pulmonary
Transdermal
Buccal
Rectal/Vaginal
Desired Release
Characteristics
Immediate release
Sustained
Release
Modified Release
e.g. enteric
Delivered Dose of
Drug
High Dose
Low Dose
Manufacturing
Process Requirement
Direct
compression
Wet Granulation
Fluid Bed
Coating/
Granulation
Spray Drying
Other novel
processes
Vidya Joshi in WWW.DrugDeliveryTech.com
May 26, 2011 31
What are Characteristics of an Ideal
Drug Candidate?
Molecular properties – MW, molecular surface area, size, charge (pKa), H-binding potential
Stable and Soluble* - formulatable
Low toxicity (ideal > 10 - fold safety margin)
Good bioavailability
Similar metabolism in humans to a species under investigation
Stable or single polymorph for solid oral dosage form
* When the solubility of an API is less than 0.1 mg/ml, the optimization of
the particle size during preformulation may be critical to efficacy or
pharmaceutical equivalence. Other researchers believe that particle size
may be critical at a solubility of 1 mg/ml or less.
May 26, 2011 32
What is Pre-formulation?
According to PQRD / USFDA
The goal of pre-formulation is to “investigate critical
physicochemical factors which assure identity, purity of drug
substances, formulatability, product performance and
quality”
Pre-formulation is an exploratory activity and interface
between Drug Substance (Solid / Liquid State Organic Chemistry)
and Drug Product (Solid / Liquid State Pharmaceutical Chemistry)
(i.e. it’s not only about stability and solubility)
PQRD – Product Quality Research Division
May 26, 2011 33
What is Pre-formulation Objective?
“The objective of pre-formulation studies is to develop a
portfolio of information about the drug substance to serve
as a set of parameters against which detailed formulation
design can be carried out.
Pre-formulation investigations designed to identify those
physicochemical and biopharmaceutical properties of drug
substances and excipients that may influence the
formulation design, method of manufacture, pharmacology,
toxicology and PK - biopharmaceutical properties of
resulting product.”
May 26, 2011 34
What’s in Preformulation?
Pre-formulation involves the application of (bio) pharmaceutical principles to physicochemical parameters of an active drug form. or
Pre-formulation (development) provides biophysical characterization of drug – excipients matrix - an insight into physical and chemical stability of Drug Product.
The characterization of a drug molecule is a very important part of the pre-formulation phase of product development.
Pre-formulation seeks to design an optimum drug delivery system.
Daria Jouraleva, ACD Labs
May 26, 2011 35
Why Pre-formulation?
1. Dose and Release – what amount of drug substance is needed in what time?
2. Bioavailability and Toxicity – Drug performance level compared with side effects.
3. Stability and Shelf-life – To ensure quality and performance during storage.
VIA REGULATORY AGENCY
External : End-Use Properties of Drug Product
Generic Drug Product should be Pharmaceutical and Therapeutic Equivalents with Same Clinical Effect and Safety
Profile.
May 26, 2011 36
Reducing set-backs (risks) during development and maximizing chances of clinical success.
The set of process - analytical activities to determine the desired (native) form to an undesirable form (upon storage) of the drug (It is a significant for formulation development).
The complete characterization, i.e. Solubility, permeability, stability, and compatibility testing at pre-formulation stage.
Why & How Pre-formulation?Internal: End-Use Properties of Drug Product
These are driving force for successful drug development –
stable formulation, analytical development & registration
application.
May 26, 2011 37
Overall Pre-formulation
Compartments (Prelim)
Patent Literature / literature searches.
Physical properties/chemical properties of API.
Powder characterization.
Chemical reactivity & forced degradation.
Excipient compatibility studies.
Vehicle selection (factorial techniques - QbD).
Package compatibility.
May 26, 2011 38
Overall Formulation Compartments
(Final)
Formulation development for early safety studies.
Physical testing of prototype.
Preliminary process identification.
Preliminary analytical development.
Prototype formulations for in-vitro studies (clinical trials).
Commercial formulation development.
The question based review (QbR) or data on drug development
and analytical development may required for scrutiny during or
after registration of application
May 26, 2011 39
Pre-formulation CharacterizationCharacterizations Techniques and Technical Tests
Stability Studies
Stress
Accelerated SSHeat, Freezing, pH, Light, Agitation,
Oxidation, Dehydration, Stress, Shear
Key Degradation
Products
Aggregation, Oxidation, Deamidation,
Cleavage, Surface adsorption, Surface
Denaturation
Stability-indicating
assays
HPLC, Electrophoresis, Spectrometry,
Particle Count, Turbidity
Physical
Chemical
Primary, secondary, tertiary, and quaternary structures, Thermal
Denaturation Temperature, Solubility, Viscosity, MW, Extinction
Coefficient, pKa, Solid State Spectroscopy & Analyzers, Salt
Selection, Polymorphs, etc.
Biological Substrate or Receptor Affinity, in vitro Bioassay
Color indicates For Biopharmaceutical Pre-formulation
May 26, 2011 40
Why Physicochemical Parameters?
Physicochemical data used to understand biological data egintestinal absorption of drug.
Drug solubility for absorption and ability of molecule to permeate barriers for bioavailability are two key properties must meet BCS and ADMET.
Parallel attention, not only to Potency, should be given to Biological (selectivity), Toxicological and Pharmacokinetics (Activity) towards target.
Attrition during drug development process is often due to inappropriate physicochemical characteristics and related poor pharmacokinetics and poor absorption.
ADMET – Absorption, Distribution, Metabolism, Excretion and Toxicity
May 26, 2011 41
Pre-formulation ParametersBulk Properties of Excipients & Drug Substances
Fundamental Properties
Secondary Properties
Crystallinity and Polymorphism
Particle Size, Shape and Surface Area
Bulk or Tapped Density
Powder Flowability
Adhesion
Compressibility or Compactability
Visio / Organoleptic
Water Adsorption
Lubricity
May 26, 2011 42
Pre-formulation Characterizes
Solubility
pKa
Partition coefficient – Log P
pH – dependent Log D
Chemical stability profile
Crystal properties and polymorphism
Particle size, shape, surface area
Specification for New Drug Substances and Products
Dosage Form Development Chart
Daria Jouraleva, ACD Labs
http://www.raell.demon.co.uk/chem/logp/logppka.html#Contents
May 26, 2011 43
Pre-formulation Parameters
Salt selection (salt forms screening, dissociation constant pKa / ionization state determination).
Solubility profiles (polar / non - polar i.e. aqueous / buffers / organic solvents) and pH dependence of solubility profile i.e. pH-rate profile.
Partition Coefficient (pH partition coefficient i.e. log p or log D), hydrophilicity and lipophilicity.
Physiochemical Properties of Drug Substances
May 26, 2011 44
Pre-formulation Parameters
Crystallization studies (impact on amorphous, particle shape, size analysis and brittleness).
Polymorph determination studies (identification, screening, relative stability – enantiotropy / monotropy, process design, and scale up to ensure that robustness of the polymorphic form, dosage method of mixture).
Drug pKa and stability information.
Solution and solid state stability.
Physiochemical Properties of Drug Substances
May 26, 2011 45
Preformulation Parameters
Chemical stability, accelerated and stress studies (heat / light / acid / base / oxidizer)
Stability profile in aq solutions (pH, buffer, solvent, temperature).
Hygroscopicity (RH – moisture sorption isotherm (formation of hydrates / deliquescence) or upon storage conditions).
Accelerated stability studies - degradation / degradation kinetics.
Thermal properties with and without excipients
Solid state stability alone and in combination with excipients.
Chemical Stability Data Studies
May 26, 2011 46
Pre-formulation Parameters
Drug (small molecules) / excipient compatibility studies (depending on dosage route).
Aqueous Solubility – solubility / dose ratio?
Order of addition and identification spectrometrically for critical process related variables.
Osmolarity measurements / aggregation phenomena.
Dissolution methodology (design composition and form according to acceptance criteria / specifications, dose and bioavailability).
Packaging compatibility studies.
Customer’s risk analysis.
Combinational Data Studies
May 26, 2011 47
Pre-formulation Instrumentation
Powder Analyzers – Optical and Laser light (flow / compaction / density / particle size / surface area).
BET (Moisture Adsorption / desorption phenomena).
Microscopy – Light and Polarized (particle morphology).
Freeze-Drying and Hot-Stage Microscopy (Melting Point)
Isothermal Heat Conduction Micro-calorimetry.
Thermal Analysis (DSC, DTGA, TMA).
Molecular Spectroscopy (FTIR / NIR / Raman / NMR, LC/MS).
X-ray Powder Diffraction (XRPD / EDAX).
Single crystal structure determination.
Solid State Characterization in Drug Development
May 26, 2011 48
Why Control Water Activity?
Water interactions with Pharmaceutical Solids Water activity (aw) influences solid-state analysis, pre-
formulation, formulation, chemical stability, manufacturing process (flow, compaction, hardness, coating), dissolution, product shelf-life properties.
Materials that have a high capacity for binding waterequilibrate more slowly to higher levels of mobile water and consequently show greater chemical compatibility with a moisture-sensitive drug than materials with lower binding capacities for water.
Free water has properties of bulk water and hence critical to chemical and physical stability of DS / DP.
Bound water (immobile) is not readily available for chemical interaction with other species.
May 26, 2011 49
Why Measure Water Activity?What is Water Activity in Pharmaceutical Dosage Form?
Water activity (aw) or Equilibrium relative humidity (ERH) is
a measure of free water (or residual or mobile or unbound
water).
Water activity (aw) is derived thermodynamically as
aw = f / fo ≡ p / po = ERH (%) / 100
f = fugacity or escaping tendency of a substance,
fo = escaping tendency of pure material
p = vapor pressure of water in material
po = vapor pressure of pure water
Water activity is a better index for microbial growth than water content.
May 26, 2011 50
Water Activity Limits: Microbial Growth
Water Activity Microorganism
<0.60 No microbial proliferation
0.61 Xeromyces bisporus (xerophilic fungi)
0.62 Zygosachharomyces rouxii (osmophilic yeast)
0.78-0.75 Aspergillus niger/flavus, Halobacterium halobium
0.84-0.81Penicillium chrysogenum/glabrum, Paecilomyces variotti,
Aspergillus fumigatus
0.86 Staphylococcus aureus
0.90 Bacillus subtilis, Saccharomyces cerevisiae
0.92 Mucor plumbeus, Rhodotorula mucilaginosa
0.93 Micrococcus lysodekticus, Rhyzopus nigricans
0.94 Enterobacter aerogenes
0.95Bacillus cereus, Clostridium botulinum/ perfringens, Escherichia
coli, Lactobacillus viridescens, Salmonella spp.
0.97 Pseudomonas aeruginosa
http://www.pharmaquality.com
May 26, 2011 51
Molecular Pre-Formulation
Scale of Science
POLYMORPHISM
‘When a substance can exist in more than one physical crystalline state it is said to exhibit
polymorphism’
A Variability Issue in Manufacturing and Stability
May 26, 2011 52
What is Active Drug Substance?
■ “Same” active
ingredient = same
active moiety and
same salt or ester
as the brand
product
■ Typically may
differ in
Polymorphic or
other physical
properties
May 26, 2011 53
What are Polymorphs?
Haleblian JK. J. Pharm. Sci. 64:1269-88 (1975)
Chemical Compound
Habit Internal Structure
Crystalline Amorphous
Single Entity
PolymorphsMolecular Adducts
Non - stoichiometric
Inclusion Compounds
Stoichiometric
Solvates (Hydrates)
Channel Layer Cage (Clathrate)
Ordered
arrangement
Disordered
arrangement
ICH Definition
on Polymorphism
May 26, 2011 54
Definition of Polymorphs
“When a solid crystalline substance can exist in more than one
physical state, it is said to exhibit polymorphism” or
“Polymorphs are drug substances that are the same active
ingredient but in different physical forms e.g.
A drug substance with different crystalline forms and a drug
substance with different waters of hydration”
How Different is Different?
Melting point
Sublimation point
Heat capacity
Conductivity
Volume
Density
Color
Morphology
Hygroscopicity
Solubility
Dissolution rate
Chemical stability
May 26, 2011 55
Allotropism vs Polymorphism
Example of Carbon “Allotropism”
Diamond Graphite Carbon Nanotube Fullerene 60
Property Particles involved Particles combine to form
Allotropism Atoms Molecules or crystals
Polymorphism Molecules Crystals
May 26, 2011 56
Method Data Measured Features
DSC, MDSC Heat flow vs Temperature Phase change during cooling + heating
TGA / DTGAChange of Mass vs
Temperature
thermodynamics difference during
dehydration or desolvation
FTIR Vibrational IR Spectrum
Molecular chemical information,
intermolecular interactions about solvent,
solvates and quantitation
Raman Raman SpectrumComplementary information to IR, No /
negligible sample preparation, quantitation
Solid State NMR Magnetic Resonance Chemical interactions, quantitation
X-RPD Diffractogram Quant/ Qualitative analysis of polymorph
MicroscopyMicroscopy under light or
electronMorphology, Textural information
Analytical Methodology
Source: Giron, D Monitoring of Polymorphism Proceedings ISIC, 13-28, 2002
May 26, 2011 57
The Principle of Molecular Vibrational Finger Print Raman
Spectroscopy
Absorbed
Scattered
…Infra Red
…Raman EffectWhat will happen?
Polymorph by Raman Spectroscopy
Laser Light Transmitted
May 26, 2011 58
Raman Scattering
Energ
y
Initial state
Excited state(Virtual)
Lig
ht
Sca
ttere
d
l0
l0
Rayleigh Scattering
l1 > l0
Dh1
Dh2
l2 < l0
Stokes Raman Scattering
Anti-Stokes Raman Scattering
Absorption
The Principle of Molecular Vibrational Finger Print
Raman Spectroscopy
May 26, 2011 59
Raman Spectrum of L-Glutamic Acid
l0
l1l2
Inte
nsi
ty
Raman Shift [cm-1]
0
=1 [cm]
l0 [nm]
1 [cm]
l [nm]-
Some Specific Peaks for α, β form can be seen!
In Dry Powder
May 26, 2011 60
Raman & X- RPD in Quantification
Mixed Glutamic Sample(Pure a-form & Pure b-form)
X-Ray Powder Diffraction
&
Raman Instrumentation
Raman can be used for quantitative analysis (dry powder) directly!
May 26, 2011 61
Why Polymorphs so Important?
P O L Y M O R P H S
Physical & Chemical Properties
Fluidity of
Powders
Dyestuff:
Colors
Bioequivalence
Bioavailability
Shape of Crystals Solubility
Quality of Products
Melting Point
Hygroscopicity
Chemical Stability
Physical Stability
Apparent Solubility
Dissolution
Manufacturability
Bioequivalence
Bioavailability
Effects of Polymorphs on Product’s Quality
Stability
Melting Point
Hygroscopicity
Chemical
Stability
Physical Stability
Apparent
Solubility
Dissolution
Manufacturability
Bioequivalence
Bioavailability
May 26, 2011 62
Polymorph Screening Approach
Tier1: Isolate crystals from single solvents. Identify binary
systems that offer control of API solubility.
Tier2: Performed controlled crystallizations in miscible /
immiscible binary systems.
Tier3: Perform non-conventional crystallizations (seeding,
vapor diffusion, varied temperatures.
Tier4: Prepare new polymorphs for solution and solid-state
characterization: solubility, stability, hygroscopicity.
May 26, 2011 63
What Factors are Important in
Polymorphism?
Hydrogen bonding ability
Presence of solvents
Degree of rigidity or floppiness of a molecule
Stabilities of low energy forms
In general, in a series of polymorphs of a compound, the polymorph with the lowest melting point is the most thermodynamically stable.
May 26, 2011 64
Polymorphic Form Conversion
During Manufacturing
Wet GranulationInter-conversions between anhydrates and hydrates, or between different hydrates
Spray – DryingAmorphous form
Milling / Micronization / Tabletting
Q. Polymorph Appearing and Disappearing?
Q. DS polymorph changes throughout a Stability Testing Period?
Interconversion among polymorphs
May 26, 2011 65
Decision Tree Development on
Polymorphism
Process for evaluating when and how polymorphs
of drug substances in ANDAs should be monitored
and controlled are:
■ Based on the ICH Guidance Q6A decision
trees on polymorphism
■ Biopharmaceutics Classification System (BCS)
May 26, 2011 66
Must Investigate Polymorphism
Decision Tree #1. Investigating the need to set acceptance criteria of polymorphs
Decision Tree #2. Investigating the need to set acceptance criteria of polymorphs for drug substance
Decision Tree #3. Investigating the need to set acceptance criteria of polymorphs for drug product
Decision Tree #4.
Part 1- Do multiple polymorphic forms exist?
Part 2 - Is routine polymorph testing of DS valuable?
Part 3 - Is routine polymorph testing of DP valuable?
Application of Decision Trees on Polymorphs
ICH Q6A: Decision Tree Criteria for Polymorphism in DS & DP
http:www.fda.gov
May 26, 2011 67
Screening Decision Tree # 1
Acceptance Criteria of Polymorphs for DS
Are there
known polymorphs
with different apparent
solubility?
NO
YES END
No further test or
polymorphic acceptance
criteria for drug
substance and drug
product
Are
all known
polymorphs highly
soluble?
NO
YES
Decision Tree # 2
START
Adequate knowledge of drug
substance polymorphs is available by
the time an ANDA is filed
Initial Elucidation
of Structure and
other Scientific
Characterization
of the Form (s):
X-RPD, DSC, TA,
Microscopy, and
Spectroscopy
http:www.fda.gov
May 26, 2011 68
Screening Decision Tree # 2
Acceptance Criteria of Polymorphs For DS
Is there a
polymorphic specification
in the USP? (e.g.,
melting point)
Set new polymorphic
acceptance criteria for
drug substance
Is the USP
polymorphic specification
adequate?
NO
YES
NO
YES
Set the same polymorphic
acceptance criteria for
drug substance as the USPDecision Tree # 3
1) Different
polymorphic form
2) Allow to establish
tight specification
Decision Tree # 1
http:www.fda.gov
May 26, 2011 69
Screening Decision Tree # 3
Acceptance Criteria of Polymorphs For DP
Is
there sufficient
concern that polymorphic
acceptance criteria for drug
product should be
established?
YES
No need to set polymorphic
acceptance criteria for
drug product
END
NO
Next Slide
Continue…
In general, there should not be a concern if
1) The most stable polymorphic form is used or
2) The form is used in a previously commercialized
product
Decision Tree # 2
http:www.fda.gov
May 26, 2011 70
Screening Decision Tree # 3 (contd)
Acceptance Criteria of Polymorphs For DP
NO
Set acceptance criteria for the
drug product dissolution testing
as a surrogate for polymorph
control in the drug product
END
YES
Previous Slide
Set acceptance criteria for the
drug product using other
approaches, such as solid
characterization method
END
Dissolution testing can frequently detect
potential conversion of polymorphs. In rare
cases, solid characterization methods have to
be used.
FDA BA/BE Guidance: “It is recommended that the
sponsor select the agitation speed and medium that
provide adequate discriminating ability, taking into
account all the available in vitro and in vivo data.”
http:www.fda.gov
Does
drug product
dissolution testing
provide adequate controls if
polymorphic ratio
changes?
May 26, 2011 71
What is it? and How BCS Works?
Allows waiver of requirement for in-vivo bioequivalence studies for IR products
The BCS (Biopharmaceutics Classification System) is a scientific framework for classifying drugs based on their aqueous solubility and intestinal permeability.
Biopharmaceutics Class Solubility
Compounds
Permeability
Compounds
I High* High
II ** Low High
III High* Low
IV Low Low
* Highly-soluble substance in a rapidly-dissolving formulation
** If Do Low ~ Highest probability of In vitro / in vivo correlation
May 26, 2011 72
Biopharmaceutics Classification System
BCS Examples B
May 26, 2011 73
Regulatory Issues : Polymorphism
1. Pre-clinical Drug Development
Identification
Early awareness of possible variations in crystalline
form
2. Early Investigational Phases (IND Phase 1 & 2)
Identification
Monitoring for possible variations in crystalline form
and solvation
Increased efforts to find polymorphs and solvates:
"polymorph screen"
http://www.fda.gov
May 26, 2011 74
Regulatory Issues : Polymorphism
3. Late Phase Drug Development (IND Phase 3 / NDA
Pre- submission)
Monitoring the manufacturing process for variations in
crystalline form, including solvates
Bulk scale-up issues: solvents, temperature, drying,
milling
Product manufacturing issues: material handling,
granulation, compaction
Control issues: dissolution, hardness
http://www.fda.gov
May 26, 2011 75
Regulatory Issues : Polymorphism
http://www.fda.gov
4. Pre-Marketing (NDA Submission and Review)
Justification of in-process controls on manufacturing
Consistent crystalline form in clinical and
bioavailability studies
Stability studies: monitoring for possible changes in
crystalline form
5. Post-Approval
Influence of manufacturing changes on the product
New bulk drug suppliers: do they manufacture the
same crystalline form?
May 26, 2011 76
Salt Screening in PreformulationWhy Salt Screening
Converting poorly absorbable free acid/base (API) form to a salt form in order to improve solubility and bioavailability.
Saltification improves physical and chemical stabilityand handleability.
of 21 New Molecular Entities approved by FDA in 2003, ten were salt forms. Exceptions are out there.
http://www.cardinal.com
May 26, 2011 77
What to be done
Selection of right counterion functionalities with optimum physico-chemical characteristics is crucial during drug development – Physical chemical properties (solubility, crystallinity, solid state stability, hygroscopicity) of New Salt Form, Processabilityunder various manufacturing conditions, and bioavailability is crucial and significant.
Analyze by High–Throughput Screening XRPD Instrument.
Salt Screening in Preformulation
Follow Decision Tree
May 26, 2011 78
Green border
indicate
processes
that may
occur in
parallel
Red border
indicate
critical
selection
criteria
Salt Screening Decision Tree
http://www.cardinal.com
May 26, 2011 79
Salt Screening Decision Tree
CRYSTALLINITY
Can crystalline salt be
prepared?
HYGROSCOPICITY
Does the salt
deliquesce at high
humidity?
SOLUBILITY
Does the salt Have
aqueous solubility?
YES
NO
ON
YES
Continue crystallization attempts
Unacceptable
NO
Solubility
enhancement
If necessary
YES
Next Slide
May 26, 2011 80
Salt Screening Decision Tree
Stability enhancement
If necessary
STABILITY
Is the salt physically
stable under
accelerated
conditions?
CONTROL
Can the process be
controlled to produce
the desired form?
POLYMORPHISM
Are there multiple
polymorphs of the salt
?
YES
YES
Ne
xt
Sli
de
He
re
NO
YES
NO
NO
Lead Candidate
FINAL SALT
Lead Candidate
FINAL SALT
SECONDARY
CANDIDATE
May 26, 2011 81
Potential of Physicochemical Property
Formulated Drug
Process of Drug Dissolution in a Dosage Form
Solubilized Drug Absorbed Drug
Drug Particles
Kdd Kprecip
Kid
Kdd = Rate of Disintegration
Kprecip = Rate of Precipitation
Kid = Rate of Intrinsic Dissolution
When Kdd > Kid, dissolution is Intrinsic Dissolution Controlled and physical
attributes of the active pharmaceutical ingredients are Important. When
Kdd < Kid, dissolution is disintegration Controlled and the cohesive properties
of the formulation are important. When Kdd ≈ Kid, dissolution is
Intrinsic Dissolution and disintegration Controlled and both cohesive and
physical properties may be important.
Source: Cynthia Brown et al Pharma Technology 2004
May 26, 2011 82
Potential of Physical Property
is the acid-base ionization constant indicating a
molecule or ion is likely to keep a proton at its
ionization centre
pKa
Log Pis the water – octanol / liposome partition
coefficient indicating a molecule will prefer an
aqueous or organic phase. Log P is a means to
understand relationship between solubility and
permeability with respect to pH
Log Dis used for ionizable drugs. It is the ratio of
concentration of all forms (ionized + unionized)
dissolved in the two phases. It is a combination
of pKa and Log P. It produces an apparent
partition coefficient for any pH value
May 26, 2011 83
Why is pKa Important? Information on pKa reflects molecular state of stability over
the pH range (e.g. stomach and blood pH ).
Neutral molecules are easily absorbed while ionized
molecule can affect drug-receptor binding pathway.
Ionized molecules remain in plasma and are cleared by
renal excretion (Ampholytes have special properties).
Most drug molecules (60-70%) contain Ionizable groups that
ionize in solution. This group belongs to Lipophilicity,
permeability & solubility class are pH dependent – a factor
in drug transport & absorption.
pKa is required in drug formulation for the choice of counter-
ion and excipients.
pKa must be recorded for regulatory compliance (either by
Gradient Titrator or Spectroscopic Techniques).
May 26, 2011 84
Why is pKa Important?
Combination of ionizable
groups in the molecule
% from above number
1 Base, no Acid 42
2 Base, no Acid 25
1 Acid, no Base 12
1 Acid, 1 Base 8
2+ Acid, no Base 3
1 Acid, 2+ Base 4
2+ Acid, 1 Base 3
Others 3
Distribution of Ionizable compounds (32,437) in World Drug
Index (51,596 compounds) 1999
Commercial available drugs are 2/3 ionizable molecules with bases only
May 26, 2011 85
Why Log P (Partition) is Important?Biological membranes are lipoidal in nature, rate of drug transfer for passively absorbed drugs is directly related to lipophilicity of molecule. Partition coefficient (water/ octanol or chloroform or liposome) is a measure of a drug's lipophilicity and an indication of its ability to cross cell membranes.
The partition coefficient is the ratios between concentrations of substances in two immiscible phases i.e. organic and aqueous phases at equilibrium.
Po/w = (C oil / C water) equilibrium
The lipophilic/hydrophilic balance - a contributing factor for the rate and extent of drug absorption. It is the best predictor of absorption rate, the effect of dissolution rate, pKa, and solubility on absorption must not be neglected.
Drugs with Po/w greater than 1 are classified as lipophilic otherwise are indicative of a hydrophilic drug
May 26, 2011 86
Polarity and Partition Relation
The partition coefficient of a drug depends upon both polarity and size.
Drugs with high dipole moment, even though un-ionized, have low lipid solubility and, hence penetrate poorly.
Ionization reduces lipid solubility as well as slows down the movement through charged membranes. (Tip: ionized molecules do not penetrate membranes. In such cases, membrane transport carriers that neutralize the charge or shield the molecule are required for absorption).
Log P is used in QSAR studies and rational drug design as a measure of molecular hydrophobicity.
May 26, 2011 87
Why is Lipophilicity Important?The lipophilicity of a drug provides a rough guide to its
pharmacokinetic dynamics
Log D at pH 7.4 Implications for drug development
Below 0Intestinal and CNS permeability problems
Susceptible to renal clearance
0 to 1May show a good balance between permeability and solubility
At lower values, CNS permeability may suffer
1 to 3Optimum range for CNS and non-CNS orally active drugs
Low metabolic liabilities, generally good CNS penetration
3 to 5 Solubility tends to become lower. Metabolic liabilities increase
Above 5Low solubility and poor oral bioavailability, although potency may still
be high
John Comer, Sirius Analytical Instruments Ltd
May 26, 2011 88
Why is Permeability Important?
Permeability (cm/sec) value
depends on the nature of
phases and API molecule
Permeability of a molecule in
vitro study may relate to
absorbability in body fluid
A relationship between
permeability and lipophilicity
Ideal drug candidates fall on
curve
John Comer, Sirius Analytical Instruments Ltd
Permeability, the rate at which a compound
will pass through a membrane
May 26, 2011 89
Why is Permeability Important?
Drug permeability either by passive diffusion
(natural) or active / facilitated / ion-pair / pore
diffusion or pinocytosis transport
High permeability is defined as human absorption
of 90% or more of administered dose
*Source: http://www.health.wits.ac.za/pharmacy/bio-adsorb.ppt#14
May 26, 2011 90
Why is Solubility Important?Definition of Solubility
The amount of a substance (solid) that dissolves in a given (specified) volume (amount) of solvent (liquid) at a specified temperature and pH or to form a saturated solution at any temperature.
Significance of Solubility
Drug’s physical entity need to be in solution form to interact with biological systems.
Active’s solubility is an important parameter for dissolution, bioavailability, and therapeutic efficacy.
Poorly soluble molecules rarely constitute successful drug – difficult to absorb / formulate and analyze.
It’s difficult to predict accurately - Early screening is vital
May 26, 2011 91
Why is Solubility Important?
Solubility is a property of API and its salt form.
Solubility is determined by measuring. concentration of equilibrated saturated solution at 37 ºC for 1 – 24 hrs.
Equilibrium time depends on test duration time as well as the physical and chemical stability (conversion of salt form to free base in vitro) of the drug.
Low-solubility compounds are compounds whose highest dose is not soluble in 250mL or less aqueous media from pH 1.2 – 7.5 at 37 ºC.
Significance of Solubility
May 26, 2011 92
Solubility : Discovery vs Development
Solubility in Discovery Solubility in Development
Turbidimetric Solubility Thermodynamic Solubility
Non crystalline Crystalline
Solids not Characterized Polymorphs Characterized
Solubilized in DMSO Solubility measured in term of a solid
Added to stirred gavages medium Equilibrated with an aqueous medium
A time scale measured in tens of
minutes
A time scale of 24-48 hours
Used for early in vivo SAR Used to determined the minimum
absorbable dose, dissolution rate, and
salt selection
Correlation with in vivo animal Correction with clinical dosage form
Better in early discovery Essential in development
May 26, 2011 93
Solubility at EquilibriumSolubility of a molecule in solvents (and some oils if the molecule is
lipophilic) is determined by the equilibrium solubility method, which
employs a saturated solution of the material, obtained by stirring an excess
of material in the solvent for a prolonged period until equilibrium is
achieved.
Common solvents used for solubility determination are
Water
Polyethylene Glycols
Propylene Glycol
Glycerin
Tweens
Castor Oil
Peanut Oil
Sesame Oil
Polysorbates
Ethyl Alcohol
Methanol
Benzyl Alcohol
Isopropyl Alcohol
Sorbitol
Buffers at Various pHs
May 26, 2011 94
Solubility Assay Methodology
Traditional Shake Flask Assay Method
Costly, time consuming, polymorphic information required,
good for development
Kinetic Assay Method
Relatively fast (96, 384 well plate) and automated
Enhanced solubility and Kinetic due to DMSO
Crystal lattice energy disappear and high energy state
solution
Informative about rank of equilibrium solubility
May 26, 2011 95
Solubility Solkin Method
May 26, 2011 96
Compounds in DMSOFactors Affect Stability / Solubility in DMSO
Storage time, Temperature, Concentration, Freeze / Thawing, Water Uptake
Once a compound crystallizes from DMSO it will not easily re-dissolve (crystallized compound is in a lower energy less DMSO soluble form)
Freeze thaw cycles increase the probability of crystallization
Narrow working window (time window) for keeping most compounds dissolved in DMSO (1 to 2 days at room temperature because compounds are active when freshly made but not when stored
May 26, 2011 97
Compounds in DMSO
Fresh DMSO is highly hygroscopic (5% water in 2hrs)
DMSO has a high dielectric constant
DMSO doesn’t solvate hydrocarbons e.g. hexane is immiscible in DMSO
DMSO solvates compound dipoles - almost all drugs have dipoles
Solvation is easier to do in DMSO than in water - no H-bond donor / acceptor networks to disrupt
DMSO containing 9% water is unfrozen in the typical lab refrigerator
Compounds Differ in DMSO Solubility Based on Crystalline Form - Amorphous is the highest energy form (most soluble in DMSO lowest melting point)
May 26, 2011 98
Solubility Kinetic Method
Kinetic
Solubility
May 26, 2011 99
Drug Solubilization: Decision Tree
May 26, 2011 100
Solid-State Stability
Elevated temperature Studies
Stability under High-Humidity Conditions
Photolytic Stability
Oxidative Stability
Solution-Phase Stability
Light Stability
Oxidation
pH-Rate Profile
Compatibility Studies: Stability in Presence of Excipients
Thin-layer chromatography
Differential thermal analysis
Diffuse reflectance spectroscopy
Typical Stability Protocol for a New Chemical Entity
Next Slide….
Chemical Stability Profile
May 26, 2011 101
General Case for Drug Substances
Study Storage Conditions Minimum Time Period at Submission
Long Term
Intermediate
Accelerated
25 °C ± 2 °C / 60% RH ± 5% RH
30 °C ± 2 °C / 60% RH ± 5% RH
40 °C ± 2 °C / 75% RH ± 5% RH
12 months
6 months
6 months
Stability Testing of New Drugs and Products
Drug Substances Intended for Storage in a Refrigerator
Study Storage Conditions Minimum Time Period at Submission
Long Term
Accelerated
5 °C ± 3
25 °C ± 2 °C / 60% RH ± 5% RH
12 months
6 months
Drug Substances Intended for Storage in a Refrigerator
Study Storage Conditions Minimum Time Period at Submission
Long Term -20 °C ± 5 °C 12 months
Chemical Stability Profile
May 26, 2011 102
General Case for Drug Products
Study Storage Conditions Min. Time Period at Submission
Long Term
Intermediate
Accelerated
25 °C ± 2 °C / 60% RH ± 5% RH
30 °C ± 2 °C / 60% RH ± 5% RH
40 °C ± 2 °C / 75% RH ± 5% RH
12 months
6 months
6 months
Stability Testing of New Drugs and Products
Aqueous Based Products Packaged in Semi-Permeable Containers
Study Storage Conditions Min. Time Period at Submission
Long Term
Intermediate
Accelerated
25 °C ± 2 °C / 40% RH ± 5% RH
30 °C ± 2 °C / 60% RH ± 5% RH
40 °C ± 2 °C / NMT 25% RH
12 months
6 months
6 months (water loss after 3 months)
Aqueous Based Drug Products intended for Storage in a Freezer
Study Storage Conditions Min. Time Period at Submission
Long Term -20 °C ± 5 °C 12 months
Chemical Stability Profile
May 26, 2011 103
Stability Testing of New Drugs and Products
Relative Humidity Ratios Calculation
Alternative Humidity Nominated Humidity Ratio
40% RH
60% RH
75% RH
25% RH
40% RH
25% RH
2.4
1.5
3.0
Aqueous Based Drug Products intended for Storage in a Refrigerator
Study Storage Conditions Min. Time Period at Submission
Long Term
Accelerated
5 °C ± 3 °C
25 °C ± 2 °C / 60% RH ± 5% RH
12 months
6 months
Chemical Stability Profile
May 26, 2011 104
http://pubs.acs.org/subscribe/journals/mdd/v06/i01/pdf/103toolbox.pdf
PAMPA - Parallel Artificial Membrane
Permeability Assay: Same size
chamber separated by filter coated
with lipid in organic solvent
Results vary if lipid selection varies.
Easy and results are comparable
with Caco-2
Coco-2: Different compartmental
volume separated by a monolayer of
cells grown on a filter.
Stable monolayer preparation time
and cost consuming.
Results agree with human in vivo
jejunal permeability experiments
Permeability Assay Methods
May 26, 2011 105
GI M
em
bra
ne
Drug
Absorbed
into
Systemic
Circulation
Do
sa
ge
Fo
rm
Prim
ary
Dru
g
Pa
rtic
les
Dis
pe
rse
d
Gra
nu
les
Disintegration
Dispersion
Dis
so
lutio
n
Drug Delivery : Solid Dosage Forms
Drug
In
“Solution”
in
GI
Media
Modified from Michael J. Hageman, Pfizer Global R&D, NJ, USA
Molecular Transport and Cellular Controlled Diffusion
May 26, 2011 106
h
D
C0Donor
solution
K
DonorReceptor
CdC1
C2
Cr
Do excipients alter or affect permeability / Absorption?
≈?
≠?
≡?
Permeability Assay Methods
May 26, 2011 107Anand Sistla in Mol. Dev. Intern Symp 2003
Drug Diffusion
May 26, 2011 108
High Low
200
0
100
300Solubility?
Dose??
?
?
?
low high
<200 >200
Solubility Decision Trees
May 26, 2011 109
Basic Powder Properties
May 26, 2011 110
ICH Q6A : Particle Size Distribution (DS) Acceptance Criteria
1. Is the particle size critical to dissolution,
solubility or bioavailability?
2. Is the particle size critical to drug
processability?
3. Is the particle size critical to drug product
stability?
4. Is the particle size critical to drug product
content uniformity?
5. Is the particle size critical for maintaining
product appearance?
NO
YES
If NO to All
If YES to All
No drug substance
particle size
acceptance criterion
required for solution
dosage form
No acceptance
criterion required
Set Acceptance
Criterion
Is the drug product a solid dosage form
or liquid containing un-dissolved drug
substance?
PSD for DS : Decision Tree
May 26, 2011 111
Homogeneity – Increases
Crystallinity – Decreases
Bulk density – Decreases
Flow characteristics – Worsens
Solubility – Increases
Reactivity – Increases
Taste – Increases
Explosiveness – Increases?
Source: Elizabeth B Vadas Inscitech Inc
Influence of Particle Size Reduction
on Material Characteristics
May 26, 2011 112
Processing factors – Micronization, grinding, milling, spray drying, lyophilization, compaction force.
Physical factors – Temperature, humidity, and pressure.
Chemical factors – Solvation (Formation of agglomerates, inclusion complex and hydrophobic film.
Dissolution in vivo will not likely to be rate limiting, if excipients are well characterized under various conditions.
High permeability attribute reduces the risk of bio-in-equivalence.
The changes in drug structure and dynamics over time needs to be verified by solid-state NMR, FTIR, Raman, X-ray
diffraction, and DS calorimetric techniques.
Effect on Dissolution, Solubility and Stability
Drug Excipient Interactions
May 26, 2011 113
log for acids
u
a
i
CpK pH
C
log for bases
i
a
u
CpK pH
C
Biophysical Significance of Theory in ADMET
Solvation – Ionization – Diffusion - Receptor – Interaction
The pKa of the drug and pH of the GI tract fluid and the pH
of blood stream control the solubility of drug i.e. rate of drug
transfer or absorption through membranes
Only non-ionized drug get through lipid membrane i.e.
unionized drugs have higher lipid solubility
Brodie’s distribution is related to Henderson - Hasselbach
equation for weak acids and bases
Henderson - Hasselbach Equation
Brodie’s pH Partition Theory
May 26, 2011 114
Types of packaging systems – storage, shipping, or marketing.
Applicable cGMPs – equipment construction, qualification applies regardless of holding time.
Description information – construction material, label information.
Suitability information – protection, compatibility, safety, performance.
Quality control information – chemical composition, physical characteristics, acceptance criteria.
Stability information – shelf life stability, expiration date, CMC documentation.
Package Compatibility
May 26, 2011 115
Thank You
May 26, 2011 116
“If we can’t describe scientifically and technologically what we are
doing as a process, we don’t know what we’re doing”