The document discusses preformulation studies, which characterize the physicochemical properties of drug substances. Some key points: - Preformulation studies are conducted early in drug development to understand how a drug's properties will influence formulation, stability, bioavailability and the development process. - Areas of study include bulk properties, solubility, stability and more. Properties like solubility, dissolution, polymorphism can impact the drug's performance. - Various analytical techniques are used to characterize aspects like crystallinity, particle size, hygroscopicity and more which provide essential information for designing drug products. - Understanding a drug's properties is important for selecting excipients, manufacturing processes, container closure systems and developing analytical

1. Preformulation Studies
By Prinsy Rana,
MM College of Pharmacy
Mullana,Ambala

2. Outline of topic
Study of physical properties of drugs like physical
form, particle size, shape, density, wetting,
dielectric constant, solubility, dissolution,
organoleptic properties and their effect on
formulation, stability and bioavailability.
Study of chemical properties of drugs like
hydrolysis, oxidation – reduction, racemisation,
polymerization and their influence on formulation
and stability of products.
Study of prodrugs in solving problems related to
stability, bioavailability and elegancy of
formulation.

3. Introduction
Preformulation:
• a stage of development during which the
physicochemical properties of drug substance are
characterized.
When???
• If the drug shows sufficient activity in animals & is
to be evaluated in humans.
Focus……
• On physicochemical properties of a new compound
which may affect the drug performance &
development of efficacious dosage form.

4. Drug Development Cycle

5. The Drug Development Cycle ~ An
Overview
The process of developing a new drug can take between
10 and 15 years with an estimated average cost of $800
million
Discovery/Pre-Clinical Testing
Time: 6.5 Years
Phase I
Time: 1.5 Years
Phase II: Safety and Efficacy
Time: 2 Years
Phase III
Time: 3.5 Years
Marketing Approval Process
Time: 1.5 Years

6. Introduction
Project team – Representative from
different disciplines
Different Disciplines
Medicinal Chemistry and Pharmacology
Pre-formulation Research
Formulation development
Process R&D
Analytical R&D
Toxicology and drug metabolism

7. Development of a drug
candidate
Deficiency – Molecular modificationto
improve drug properties
Salts eg. Ephedrine HCl
Prodrug eg. Erythromycin Estolate
Solvates, polymorphs etc
Synthesis organic media – Purity

8. Compound Identity
Structure
Formula & Mo. Wt.
Therapeutic Indication
•Probable Human Dose
•Desired Dosage Form(s)
•Bioavailability Model(s)
•Comparative Products
Potential Hazards
Initial Bulk Lots
•Lot Number
•Crystallization Solvent(s)
•Particle Size Range
•Melting Point
•% Volatiles
•Observations
Analytical Methods
•HPLC Assay
•TLC Assay
•UV/VIS Spectroscopy
•Synthetic Route
•Probable Decay Products
Key Dates
•Bulk Scale up
•Toxicology Start Date
•Clinical Supplies Preparation
•IND Filing
•Phase I Testing
Critical development Issue(s)
Essential information helpful in designing preformulation evaluation of a new drug
I
II
III
V
VI
IV
VII
VIII
IX

9. Drug Discovery Literature Search
Preliminary Data
•Stability assay
•Key Stability Data
•Key solubility Data
Molecular Optimization
Salts& solvates
Prodrugs
Evaluation & Selection of
Drug
Formulation Request
Physical
Characterization
•Bulk properties
•Solubility profile
•Stability profile
Formulation
Development
•Compatibility & Stability
•Dissolution
•Bioavailability
Phase I
Formulation
•IND Stability
•Bioavailability
•Scale-up
Investigational New Drug (IND) Application
Process Research
•Improve Yield
•Alternate route
•Produce bulk
Process Development
•Bulk scale-up
Analytical
Research
•Assay development
Analytical Research
•Bulk clearance
•Toxicity potency
•Formulation assay
•IND formulation
stability
Bioavailability
•In-vivo models
Toxicology
•Acute
•Chronic

10. Preformulation studies are an important foundation
tool early in the development of both API and drug
products.
They influence….
Selection of the drug candidate itself
Selection of formulation components
API & drug product manufacturing processes
Determination of the most appropriate container /
closure system
Development of analytical methods
Assignment of API retest periods
The synthetic route of the API
Toxicological strategic management process
Why preformulation studies are
required?

11. Preformulation Characterization
Bulk properties
Organoleptic
crystallinity and polymorphism
water adsorption
particle size, shape, and
surface area
bulk density
Adhesion
powder flow
compressibility
Physico-chemical properties
solubility analysis
Ionization
partition coefficients
dissolution
Stability
•solid state (RH, oxygen, light, compatibility)
•solution (pH, buffers, solvent, temperature)
•compatibility with excipients (other additives)
Biopharmaceutical properties
•absorption (route, rate, extent, mechanism,
absorption windows, food effects)
•metabolism (first pass metabolism, enzyme
induction, metabolism in GIT)
•duration of action (dosing, controlled release)
•dose

12. Any Questions

13. Investigative Procedures on
Pre-formulation Characteristic
contents as Examples

14. Objective
Quantitation of physical chemical
properties that will assist in developing a
stable, safe and effective formulation with
maximum bioavailability

15. Principal areas of
Pre-formulations
BulkCharacterization
SolubilityAnalysis
StabilityAnalysis

16. Principal areas of Preformulations
Bulk Characterization
Crystallinity and polymorphism
Hygroscopicity
Fine particle characterization
Bulk density
Powder flow properties

17. Bulk Characterization
Synthetic process simultaneously developed
A drug candidate – Solid form not identified –
emerge of new polymorphs
Solid form – particle size, bulk density and
surface morphology – Process development
Comprehensive characterization – To avoid
misleading predictions of stability or solubility,
which depends on a particular crystalline form

18. Crystallinity and polymorphism
Crystal habit and the internal structure
affects the bulk and physiochemical
properties
Flowability to chemical stability
Habit – Description of the outer
appearance of a crystal
Eg: Acicular or needle, platy, massive,
tabular etc
Internal structure : Molecular
arrangement within the solid

19. Crystallinity and polymorphism
Changesin internal structure for acompound – Alter
changein the crystal habit.
Characterisation Involves –
Verifyingthe solid isthe expectedchemical compound
Characterization the internal structure
Describingthe habit of the crystal
Prismatic
Bladed

20. Habit and Crystal chemistry of a
compound
Chemical Compound
Habit Internal structure
Crystalline
Single entity
Polymorphs
Molecular Adducts
Non Stoichiometric inclusion
compounds
Stoichiometric
Solvates
(Hydrates),
Layer Channel
Cage
(Clathrate)

22. Crystallinity and polymorphism
Crystals
Repetitious spacingof constituent atomsor molecules
in 3 dimensional array
Amorphous
Have atoms or moleculesrandomlyplaced, prepared by
Rapid precipitation
Lyophilization
Rapid coolingof liquid melts
Amorphous – Higher thermodynamicenergy,
solubilites and dissolutions isalso high.
Upon storage – Tends to revert morestable forms
Disadv.:Thermodynamic instability

23. Crystallinity and polymorphism
Crystalline–
Nonstoichiometric adducts – entrapped solvents within
crystals.Eg.: Inclusions
Undesirable, Lackof reproducibility – Avoided
Stoichiometric adducts – As a solvate, is a molecular
complex that has incorporated the crystalline solvent
moleculesinto specificsiteswithin crystal lattice
Eg.: water( hydrate- monohydrate)
Aq. Solubilities,Eg Ampicillin
Dissolution - bioavailability

24. Crystallinity
Conversion of ananhydrous compound to ahydrate
within the dosageform mayreducethe dissolution
rate &extentof drug absorption.

25. Polymorphism
Ability of a compound or element to crystallize as more than one
distinct crystalline species with different internal lattices.
Chemical stability and solubility – Drug’s bioavailability
Physicochemical parameter that alter
Melting point
Density
Hardness, crystal shape, optical properties
Eg.: Chloramphenicol Palmitate
3 crystalline polymorphic forms, A,B,C and amorphous form
Physicochemical properties vary : MP, Density,
hardness, optical properties etc

26. Polymorphism
Chemical stability & solubility changes
due to polymorphism can have an impact
on drug’s bioavailability & its development
program.
e.g. Chloramphenicol Palmitate exist in 3
crystalline polymorphic forms (A, B & C),
“peak” serum levels increased substantially as
a function of the % of form B polymorph, the
more soluble polymorph.
Characterization of polymorphic &
solvated forms involves quantitative
analysis of these differing
physicochemical properties.
% of Form B

27. Polymorphism
Classification-
1. Monotropic polymorphs - one stable crystal form and
one meta stable regardless of temperature change
OR
Only one polymorph is stable at all reasonable Temp.
Eg. Glyceryl stearates,metalazone
2. Enantiotropic polymorphs - One polymorph is stable
over one temperature range, another polymorph is
stable over a different temperature range
E.g. carbamazepine andacetazolamine,Sulfur

28. Polymorphism
Preformulationstudy-
- identifies polymorph stable at room
temp
- stability of polymorph in dosageform
Analytical Method Material
req.
Microscopy 1mg
Fusion Method 1mg
DSC 2-5 mg
IR 2-20 mg
X-ray powder diffraction 500 mg
SEM 2 mg
TGA 10 mg
Dissolution/ solubility analysis Mg to gm

29. Analytical method for
characterization of polymorph
1. Microscopy-

30. Hot stage microscopy
Micrographs taken at a heating rate of 108C/min
(a) 30.08C, (b) 156.58C, (c) 162.58C, (d) 166.28C,
(e) 168.58C and (f) 170.58C.

31. Thermal Analysis
1. DSC- measures Heat Loss/ Gain resulting
from chemical or physical changes
2. TGA- measures changes in sample
weight as a function of time/ temp
Eg. Endothermic reaction-
Exothermic reactions-
Eg. Anhydrous, Dihydrate form

33. 3. X-ray diffraction
When X-rays interact with a crystalline
substance (Phase), one gets a diffraction
pattern. The X-ray diffraction pattern of a
pure substance is, therefore, like a fingerprint
of the substance.
4. Additional techniques used are- NMR, SEM,
IR

34. Scanning electron microscopy
(SEM)

35. Hygroscopicity
Factors
Adsorption & equilibrium moisture content depends upon
Atmospheric humidity
Temperature
Surface Area
Exposure & mechanism for moisture uptake
Types
Deliquescent: adsorbs sufficiently water to dissolves completely
Hygroscopic: adsorb water and forms hydrate
Changes in moisture level affects
Chemical stability
Flow ability
Compactibility

36. Hygroscopicity
Normalized or percentage weight gain data from
these hygroscopic studies are plotted against
time to predict stability studies.
Karl Fischer titration, gas chromatography, TGA
Based on data, Specific handling during
manufacturing (Humidity control) / special
storage (Dessicant)can be recommended.

37. Fine Particle Characterization
Bulkflow,formulation homogeneityand surfacearea
controlled processessuchasdissolution.
Microscopy
Coulter counter
Sieve method
BET method (Surface area)
SEM method

38. Coulter counter
A Coulter counter is an apparatus for counting and
sizing particles suspended in electrolytes.
A typical Coulter counter has one or more
microchannels that separate two chambers containing
electrolyte solutions.
As fluid containing particles or cells is drawn through
each microchannel, each particle causes a brief change
to the electrical resistance of the liquid.
The counter detects these changes in electrical

39. BET method
Braunner, Emmett and Tellermethod
Layer of nitrogen is adsorbed on the
sample surface at -196°C (until surface
adsorption reach equillibrium)
Sample is heated to room temperature-
N2 desorbs and its volume is measured
and converted to no. of adsorbed
molecule via ideal gas law (PV=nRT)
Each N2-16A2

40. Bulk Density
Bulkdensity:
Varies with Method of crystallization, millingor
formulation
High dose– Sizeof capsules
Low dose- homogeneity
Drug and excipients
Tappeddensity
Truedensity

41. Powder Flow properties
Powder Flowproperties: Freeflowing or
cohesive
Factors affecting are-
particle size, density, shape,moisture
content, electrostatic charge
-Flow rates (g/sec)
-Compressibility Index
-Angleof repose

42. Way to improveflow properties
-Granulation
-Slugging/ compaction
-Glident

43. Any Questions

44. Principal areas of Pre-formulations-
Solubility Analysis
Ionization constant –pKa
pH solubility profile
Common ion effect – Ksp
Thermal effects
Solubilization
Partition co-efficient
Dissolution

45. Solubility Analysis
What issolubility??
Factors affectingsolubility
Saturationsolubility
What isDissolution??

46. Soluble from 10 to 30 parts
Sparingly soluble from 30 to 100 parts
Slightly soluble from 100 to 1000 parts
Very slightly soluble from 1000 to 10,000 parts
Practically insoluble more than 10,000 parts
Solubility Analysis
Very soluble less than 1 part
Freely soluble from 1 to 10 parts

47. Solubility Analysis
Solubility study done in varioussolvents
-Aqueous solvent
- water, buffers
-Nonaqueous solvents
- Organic solvents
- Glycerol, PEG

48. Solubility Analysis
Focus on drug-solvent system thatcould
occur during the delivery of the drug
candidate
Provides basis for formulationwork.
Determination of
pKa
Temperature dependence
pH solubility profile
Solubility products
Solubilization mechanisms
Rate of dissolution

49. Solubility Analysis
Analytical methods useful include
HPLC
UV Spectroscopy
Fluoroscence Spectroscopy
Reverse Phase gas chromatography
Factors to be defined for solubility and
Dissolution study -
pH
Temperature
Buffer concentrations

50. pKa Determination
Dissociation constant is capability ofdrug
to ionize within pH range of 1 to 10
Solubility & absorptionaltered
Henderson-Hasselbalchequation
Acidiccompounds
BasicCompounds

51. pKa Determination
contd..
Absorption Principles
Weakly acidic drug pka > 3, unionized form in the
stomach , Drug is ionized predominantly in
intestine.
Basic drug pka=8-10, ionized form predominantly
in stomach & intestine
Eg. Erythromycin
- Other factors like lipid solubility, dissolution rate,
common ion effects, metabolism also affects

52. pKa Determination
contd..
Determination of pKa
Analytical methods
Determination of spectral shifts by UV or Visible spectroscopy
(Dilute aq. Solution can be analyzed directly)
Potentiometric Titration
(pKa range of 3-10)
Factors affecting pKa
Buffer
Temperature
Ionic Strength
Co-solvent

53. Effect of Temperature
Solution Process
Endothermic
Heat of solution is positive
Exothermic
Heat of solution isnegative( lithium salts)
Non-electrolytes &ionizedforms ΔH between4 to 8 kcal/mol
Salt forms of drugs-2 to 2 kcal/mole (lesssensitive to temp.)
Effect solution dosageform design&storage condition.
Solventsystemsincluding co-solvents.
Micelles
Complexation

54. Heat of solution – solubility values for saturated
solutions equilibrated at controlled temperature
Range: 5°C, 25°C, 37°C, 50°C
lnS = -∆Hs/R (1/T)+C
Where S = molar solubility at temperature T kelvin
R = gas constant
ΔHs= Heat of solution
Semi log plot solubility vs reciprocal temperature
ΔHsobtained from slope
Salt forms of drugs – less sensitive ΔHs: -2 to +2kcal/mol
Unionized form of weak acids/ bases dissolved in
water ΔHs: 4-8kcal/mole

55. Solubilization
Increasing the solubility of
a drug by addition of third
agent (solubilizing agent) is
called as solubilization
Addition of co-solvent to
the aqueous system like
ethanol, propylene glycol, &
glycerin
Act by disrupting the
hydrophobic interactions at
the nonpolar solute/water
interface. Fig: Solubility of hydrocortisone & hydrocortisone 21-
heptonoate in propylene glycol-water mixtures

56. Partition Coefficient
Ratio of unionized drug distributed
between the organic & inorganic aqueous
phase at equilibrium.
Importance
Screening for biological activity
Drug delivery
System usedare
Octanol/water and Chloroform/water

57. pH Solubility Profile & Common Ion
Effects
Solubility of an acidic or basicdrug
depends on
pKa of the ionizing functional group &
intrinsic solubilities for both the ionized &
unionized forms.
Experimental determination of a solubility
product should include measurement of
pH as well as assays of both drug &
counter ion concentrations.

58. Dissolution
Release of drug from a dosage form involves diverse factors
as:
A drug is expected to be release from the solid dosage forms
(granules, tablets, capsules etc) & immediately go into
molecular solution. This process is called dissolution.
Dissolution (molecular dispersion) is a prerequisite for the
drug absorption.
APPLICATION
The dissolution test is used as a quality control tool to monitor
routinely the uniformity & reproducibility of production batches.
The test is utilized as a research tool for optimizing the parameters
& ingredients in new formulations.
Whenever in vitro & in vivo correlation are observed, the dissolution
studies are used as tools to substitute the frequent studies of
bioabsorption.

59. Dissolution contd…
Dissolution is expressed in terms of a rate process.
Greater the rate, faster the dissolution.
Dissolution rate may be defined as “the amount of drug
substance that goes into solution per unit time under
standardized conditions of liquid/solid interface,
temperature & solvent composition”.
Noyes-Whitney’s equation is useful for estimating the
rate of dissolution.
dC / dt = DA/ hV (Cs -C)
DISSOLUTION TESTING CONDITIONS
Apparatus
Dissolution Medium
Agitation
Validation

60. DISSOLUTION APPARATUS
The most commonly employed dissolution test methods
are (1) the basket method (Apparatus 1)
(2) the paddle method (Apparatus 2)
The basket and the paddle methods are simple, robust,
well standardized, and used worldwide. These methods
are flexible enough to allow dissolution testing for a variety
of drug products.
Apparatus 1 and Apparatus 2 should be used unless
shown to be unsatisfactory.
The in vitro dissolution procedures, such as
(3) the reciprocating cylinder (Apparatus 3) and
(4) a flow-through cell system (Apparatus 4)
described in the USP, may be considered if
needed.
These methodologies or other alternatives/modifications
should be considered on the basis of their proven
superiority for a particular product.

61. Dissolution
basket method
(Apparatus 1)
Paddle method
(Apparatus 2)
reciprocating cylinder
(Apparatus 3)
flow-through cell
system (Apparatus 4)

62. Any Questions

63. Principal areas of Preformulations
StabilityAnalysis
Stability in toxicology formulations
Solubility stability
pH rate profile
Solid state stability
Bulk stability
Compatibility

64. Stability Analysis
StabilityAnalysis requirement
Stability in toxicology formulations
Solution stability
pH rate profile
Solid state stability
Bulk stability
Compatibility

65. Stability Analysis
Preformulation studies givefirstquantitative
assessment of chemicalstability of anew drug.
Solution State Solid
State
Handling, formulation, storageand administration of
adrugcandidate
Test protocols &experimentalmethods
Assay– intact drug and degradedproduct
Evaluation – HPLC, Gas Chromatography

66. Stability in toxicology
formulations
Sincetoxicological studies typicallycommenceearlyin drug
development,it isoften advisableto evaluatesamplesof
toxicologypreparations for Stability and potential
homogeneity problems
Drug administered – Feed or oral gavageof solution or
suspension of drug in an aqueousvehicle
Minerals,vitamins,enzymes,amultitude of functional
groups present in feed– reducesshelflifeof drug
Freshsampleof feedto be used
Solution or suspension – Checkedfor easeof manufacture
Stored in a flame sealed ampoules at various temperatures
Occasionalyshaking– Dispersability

67. Solution Stability
Aim- Identification of conditions necessaryto form astable
solution
Study Includes– effectsof pH, Ionic strength, Co-solvent, light ,
temperature and oxygen
Probing experimentsat extremesconditions of pH and
temperature (0.01N HCl ,water,0.01N, NaOH allat 90°C).
Assayspecificityand Maximumrates of degradation
CompletepH rate profile – pH of max stability.
Aq.Buffersareusedto provide widerangewith constant levelsof
drug, cosolvent and ionic strength
Compatible with physiological media
Eg.:Ionic strength ( µ) of 0.9% NaCl is 0.15
Equation: µ = ½∑miZi2
mi=molar conc.of the ion, with valence Zi

68. Solution Stability
Procedure-
Stability solutions :Flint glassampoules,flamesealed–
preventevaporation, Stored at temperature not exceeding
its BoilingPoint (if organicco-solvents are used).
Varied temp-Activation energy
Light stability – protective packing
Amber– yellow–greenglasscontainers
Wrapped in aluminiumfoil or cardboard packages
Potential for oxidation:
ExcessiveheadspaceofO2
Excessiveheadspacewith inert gas
Inorganicantioxidant – Sodium metabisulfite
Organic antioxidant – Butylatedhydroxytoluene BHT

69. Solution Stability
pH rateprofile
Stability data at eachpH and temperature
Analyzedkinetically – apparent decay constant
Arrhenius plot – logof apaprent decayrate constantVs
reciprocalof absolute temperature
Energy of activation

70. Solid state stability
Aim: Identifications of stable storage
conditions for drug in the solid state and
identification of compatible excipients for
a formulations.
Affectedbychangein purity and crystallinity
Initial bulk lots and newerlots– to be studied
Solid state isslowerand difficult to interpret than solution
state
TLC, UV-Vis, fluorescence
Polymorphicchanges– DSC, IR or appearancechangeslike
oxidation – surface discoloration
Procedure: Open screwcapvials– Exposedto various
conditionsTemp., Humidity and light upto 12weeks

71. Solid State Stability
Storage conditions
1. Refrigerator- 5°C
2. Room temp.- 22°C
3. Ambienthumidity, 70% RH, 90%RH
4. 25°C/60% RH, 40°C/75% RH,
5. Light- Clear,Amber,yellow-greenglass,control
sample
6. Ambienthumidity- O2 headspace,N2 headspace

72. Elevated temperature studies
The elevatedtemperaturescommonlyusedare40, 50, and
60 degreecentigrade with ambient humidity.
The samplesstored at highesttemperature areobserved
weekly forphysical and chemicalchangesand compared to
anappropriate control .
If asubstantial changeisseen,samplesstored at lower
temperature areexamined .
If no changesisseenafter 30 daysat 60°C ,the stability
prognosisis excellent.

73. Stability under high
humidity
conditions
Solid drug samplescanbeexposedto different
relativehumidity conditions bykeepingthem in
laboratory desiccatorscontaining saturated
solutions of various salts.
The closeddesiccatorsin turn arekept in ovento
provideconstant temperature.
The preformulation data of this nature are useful in
determining if the material should be protected and
stored in controlled low humidity environment or if
non aqueoussolventbeusedduring formulation.

74. Photolytic stability
Manydrugsfadeor dorpen on exposure light.
IncreasedImpurity level
Samplesshould beexposedto light providingan overall
illumination of not less than 1.2 million lux hours
and anintegrated nearultraviolet energyof not lessthan
200 watt hours/square meter
If protected samples(e.g.,wrapped in aluminumfoil) are
usedasdark controls to evaluatethe contribution of
thermally inducedchangeto the total observedchange,
theseshould be placedalongsidethe authentic sample.
Resulting data maybeusefulin determiningif anamber
colored container isrequired or if color maskingbyeshould
beusedin the formulation

75. Stability to Oxidation
Drug’ssensitivityto oxidation canbeexaminedby
exposingit to atmosphere of high oxygen tension.
Usuallya40% oxygenatmosphere allowsfor rapid
evaluation.
Samplesarekept in desiccatorsequipped with three-way
stop cocks,whicharealternativelyevacuatedand
flooded with desired atmosphere.
The processisrepeated 3 or 4 times to ensure100%
desired atmosphere.
Results maybeusefulin predicting if anantioxidant is
required in the formulation or if the final product

76. Compatibility studies
The knowledge of drug excipients interaction
isusefulfor the formulation to selectappropriate
excipients.
The describedpreformulation screeningof drug
excipientsinteraction requiresonly5mgof drug in
a50% mixturewith the excipientsto maximizethe
likelihood of obscuring aninteraction .
Mixtures should be examined for physicochemical
properties like appearance, Assay and degradation

77. Formulation Recommendation
Upon the completion of preformulation evaluation
of anewdrug candidate, it isrecommendedthat a
comprehensive report to be prepared
highlightingthe pharmaceuticalproblems associated
with this molecule.
This report should concludewith recommendations
for developingphaseI formulations.
These reports areextremelyimportant in preparing
regulatory documents&aid in developing
subsequent drug candidates.

78. Any Questions

79. Principal areas of Preformulations
Outline of topic
Study of chemical properties of drugs like
hydrolysis, oxidation – reduction,
racemisation, polymerization and their
influence on formulation and stability of
products.

80. Study of chemical properties of
drugs like
Hydrolysis
Oxidation – Reduction
Photolysis
Racemisation
Polymerization
Mechanismsof degradation and their influence on

81. OBJECTIVE
Initial investigation on chemical properties
Knowledge about the chemical and physical
stability of acandidate drug in the solid and
liquid state – drug development
Stability of formulation– shelf life of marketed
product
Chemical properties , path of degradation ,
Rate of degradation
Stability with temperature,pH, light and oxygen,a
number of experimentsneedto be performed

82. Ester Acid+ Alcohol (involvesrupture of a
covalentlinkagebetweenacarbon atom and anoxygen
atom).
Catalysts – polar nature suchasmineralacids,alkaliesor
certainenzymes– capableof supplyingH+ and OH- ions
Acid or alkalicatalysed hydrolysis
Degradation
Hydrolysis: P(
d
ar
u
tg
h)
wm
o
ao
l
ye
c
u
l
e
s
interact with water
molecule to yieldbreakdown product.
Susceptible to the hydrolytic process: esters, substituted
amides, lactones, and lactams.
Eg:Anestheics,antibiotics ,vitamins and barbiturates
1. Ester hydrolysis:
Hydrolysis

83. Ester Hydrolysis

85. Kinetic study of hydrolysisofAspirin was done
in variousbuffer solutions. It wasobservedthat Aspirin is most
stableat 2.4, at pH 5 to 7 degradation ispH independent and
abovepH 10 stability decreaseswith increase in pH.

86. Factors to be considered in Hydrolysis
pH
Type of solvent :solvent lowerdielectric constant
Eg.:ethanol,glycols,mannitol etc.
Complexation : steric or polar effects. Eg.: caffeine with
benzocaine – electronic influence of complexing agent –
alters affinity
Surfactants: nonionic , cationic , anionic stabilizes drug
against base catalysis. Eg: 5% SLS – 18folds increase in
t1/2 ofbenzocaine
Modification of chemical structure
Saltsand esters

87. Amide hydrolysis
Hydrolytic reaction results:
Amide Acid +Amine
Eg.: Chloramphenicol
Niacinamides
Ring alterations: hydrolysisproceed asaresult of
ring cleavage.
Eg. Pilocarpine

88. Oxidation - reduction
Second most common way.
Eg.:steroids, vitamins,antibiotics etc
Mediated byfreeradicals or by molecularoxygen
Complex oxidative processes
Sensitivetowards trace metal and other impurities
Redox reactions involveeither transfer of oxygen
or hydrogen atoms or transfer of electrons

89. Oxidation - reduction
Oxidation – presenceof oxygen
Initiated byheat ,light or trace metalions that
produce organic free radicals
These radicalspropagate the oxidation reaction ,
whichproceedsuntil inhibitors destroy the
radicalsor until side reactions eventuallybreak
the chain
Eg. Dopamine

90. Oxidation - reduction
Substanceisoxidized when :
If electrons areremovedfrom it
Gains electronegativeatoms or radicalsor loses
electropositive atoms or radicals
Addition of oxygenand removalof hydrogen
Most common:autoxidation (free radical chain
process)
Involveshomolyticbond fission of acovalentbond
– eachatom retains oneof the electrons of original
covalent bond:

91. Autoxidation
R. + H.
Initiation: RH
Propagation:
R. + O2
RO 2.+ RH
RO 2
ROOH + R.
Hydroperoxide decomposition
ROOH RO. + .OH
Termination
RO2. +X Inactive products
(X convertsto peroxides group)
RO2 +RO2 Inactive products
Rate of prednisolone : presence of aerobic and anaerobic
conditions
Rancidity – oilsand fats
Oxygencontent and Antioxidants
Light, heat
Activation

92. Photolysis
Photochemical
Photosensitizer
UV- violet portions – moreactive( shortet
wavelength,more energy)

93. Racemization
Racemization – compound changesoptical activity
without changingthe chemical composition.
Levoand dextro form
Eg:l-adrenalineis15-20times moreactivethan
dextro form
Racemic mixture
Stability and therapeuticactivity

94. Kinetics of degradation:
K = rate of reaction
Drug – Product
Zero ,first ,secondorder reactions, half life etc.
Effect of temperature :logk= logA–Ea/2.303RT
Depends on functional group of assymetricalcarbon
atom,aromatic grp tends to accelerate racemization

95. Any Questions

96. Prodrugs
Studyof prodrugs in solvingproblemsrelated to
Stability,
Bioavailability and
Elegancyof formulation
Principal areas of Preformulations

97. Prodrugs- Intoduction
Drugs – Undesirable physicochemicaland
biological properties
How do one improvetherapeutic efficacy?
Biological,Physicaland Chemical means
Biologicalapproach – Alters the ROA– mayor
maynot beacceptablebythe patient
Physicalapproach – Modify the designof the
dosageform Eg.: CDDS
ChemicalApproach– Bestto enhancethe drug
selectivitybyminimizingthe toxicity

98. Prodrug
3 Chemicalmeans– To optimize the drug
therapeutics
1.Designand developmentof newdrugswith
desirable features
Screeningof chemicalsfor biologicalactivity-
Clinically useful
2.Designof hard and soft drugswith desirable
characterisitcs
3. Designof prodrugs

99. Prodrug
Hard drugs:Resistant to biotransformation - Long
biologicalhalf life, no toxic metabolite formation.
Disadv.:Accumulation
Soft drugs:Abiologicallyactivedrug compound i.e
biotransformed in vivoin arapid and predictable
mannerinto non- toxic moieties.Relativelyinert
metabolites
Disadv.:Short Duration Of Action
Ex.Insulin, adrenaline
Replacementof alkylchain of drug – ester group –
readilyhydrolysedin vivo

100. Prodrug
A prodrug is chemically modified inert drug
precursor which upon biotransformation
liberates the pharmacologically active parent
compound
Pro-agent, bioreversiblederivativeor latentiated drug
Design approach – Drug latentiation
Classification
Depends on constitution, lipophilicity and method of
bioactivation and catalystsinvolvedin bioactivation
1. Carrier linked prodrugs
2. Bioprecursors

101. Carrier linked prodrugs
Simple prodrugs
Areoneswherethe activedrug iscovalently
linked to an inert carrier or transport moiety
Esters or amides
Greatly modified lipophilicity due to the
attached carrier
Activedrug releasedbyhydrolytic cleavage
either chemicallyor enzymatically

102. Carrier linked prodrugs

103. Bioprecursors
KnownasMetabolicprecursors
Are inert moleculesobtained bychemical
modifications of activedrug but do not
contain a carrier
Moiety hassamelipophilicity asthe parent
drug
Bioactivated byredox biotransformation only
enzymatically
Eg.:Arylaceticacid NSAID – fenbufen from
aroylpropionic acid precursors.

104. Bioprecursors

105. Pro-Prodrug
Fewcasesof carrier type prodrugs to beformulated as
ophthalmic, parenteral or oral liquid preparations, the
conversionto activedrug –- Chemically( non
enzymatically)triggered bychangein pH –- Stability
problems
Overcomeby :
Double prodrug or pro-prodrug concept
Further derivatized in afashion – Only
enzymaticallyconversionof prodrug ispossible
beforethe latter cancleaveto releasethe active drug
Eg.:diesters of pilocarpic acid

106. Mutual Prodrug
In contrast to simpleprodrugs wherethe carrier
usedisbiologically inert,
Prodrug comprisesof 2 pharmacologicalactive
agentscoupledtogether to form asinglemolecule
that eachactsascarrier for the other
Prodrugs of two activecompounds arecalledas
mutual prodrugs
Eg.:Benorylate:For NSAID’sof aspirin and
paracetamol

107. Examples of Prodrug
Aspirin – Produg of salicylicacid- decrease
GI irritation
Hexamine – Excreted in urine isconverted to
formaldehyde in the acidicurine pH -
Urinary tract antibacterial

108. Ideal characteristics of Prodrug
Shouldn’t haveintrinsic pharmacological
activity- Inert
Rapidly transform, chemicallyor enzymatically
into the activeform wheredesired
The metabolic fragments, apart from the active
drug should be nontoxic

109. Applications - Prodrug
PharmaceuticalApplications:
Improvement of taste
Improvement of odor
Changeof physicalform for preparation of solid
dosage forms
Reduction of GI irritation
Reduction of pain on injection
Enhancement of drug solubility and dissolution
rate
Enhancement of chemicalstability of drug

110. Applications - Prodrug
Pharmacokinetic Applications
Enhancement of bioavailability
(lipophilicity)
Prevention of pre-systemic metabolism
Prolongation of duration of action
Reduction of toxicity
Site specificdrug delivery(drug targeting)

111. Any Questions

112. Improvement of taste
Poor patientcompliances
Bitterness, acidity etc
Two approaches:Overcometaste
Reduction of drug solubility in saliva
To lowerthe affinity of drug towards taste
receptors
Eg.:Chloramphenicol – Palminate ester
Principal areas of Preformulations

113. Improvement of odor
Depends upon its vaporpressure (BP)
High v.phaslowb.p = Strong odor
Eg.:Ethyl mercaptan – foul smellat b.p
35°C
Used in treatment of leprosy,isconverted
to phthalate ester (diethyldithio-
isophthalate) higher b.p and is odorless

114. Changeof Physicalform of the drug
Liquid form – unsuitable for formulation astablet
if doseis high
Conversionof suchliquid drug into solid prodrugs
- formation of symmetricalmolecules– Higher
tendencyto crystallize
Eg.Trichloroethanol converted to
p-acetamidobenzoicacid ester

115. Reduction of GI irritation
Irritation and damageto gastric mucosa
Direct contact
Increased stimulation of acid secretion
Through interference with the protective mucosal
layer
Eg.:NSAID’s,especially salicylates
Lowersthe gastric pH and induces or aggravates
ulceration
Eg:Salicylicacid – Aspirin

116. Reduction of pain or injection
IM injection – Painful whendrug precipitates
or penetrates into the surrounding cellsor
whenthe solution isstrongly acidic,alkaline
or alcoholic
Eg.1: Lowaq.solubility of clindamycin HCl
Overcomebymorewater soluble prodrug
suchas2`-phosphate ester of clindamycin

117. Enhancement of solubility and
dissolution rate
Hydrophilicity of drug:
When dissolution israte limiting step in absorption of
poorly aq.soluble agentsor whenparenteral or
ophthalmic formulations
Hydrophilic or watersolubledrug aredesired
Eg: Drugs – OH group canbeconverted into their
hydrophilic forms byuseof half esterssuchas
hemisuccinates,hemiglutarates etc
Other half of theseacidiccarriers canform Na, Kor
aminesalts – rendersthe moietywater soluble

118. Enhancement of solubility and
dissolution rate
For alcoholic or phenolic drugs :
Steroidal drugslikecortisol. prednisolone ,
dexamethsone,the sodium succinatesalts have
poor stability and hencephosphate estersare
preferred
Eg1:Chloramphenicol – Sodiumsuccinate
ester
Eg2:Tetracycline– Tetralysine
Eg3:Diazepam– L- lysine ester

119. Enhancement of chemical stability
Adrug maydestabilize - shelf lifeor GIT Orally
Shelflife stability- IV
Conventional approach – Lyophilizesuchsolutions into
powderwhichisreconstituted before use
Improves stability
Antineoplastic drug: azacytidine
Aq.solution– hydrolyzedbut bisulfite prodrug isstableto
degradation at acidicpH and morewatersolublethan the
parent drug
Conversionat physiologicpH 7.4
Cefamandole– nafateesterprodrug – improvedshelf
life( Reconstitution from dry powder)

120. Prodrug stability
Pencillins – More susceptibleto hydrolysisand
destabilization in gastric acid
Carbenicillin – cannot beadministered orally
Its esterprodrug carindacillin (α indanol ester) and
carfecillin (α phenylester– more stable
At pH 7.0 hydrolysisreleasesthe activedrug and
absorbed
Erythromycin – stearate( ethylsuccinateand estolate )

121. Any Questions

122. Enhancement of Bioavailability
Most drugs – Passivediffusion – lipophilicity
2reasons to enhance oral bioavailability of lipophilic
compounds
Lipophilic forms – Enhanced membrane/water partition
co-efficient compared with hydrophilic form
Eg.: pivampicillin ,talampicillin prodrugs of ampicillin
are lipophilic (98%) and rapidly hydrolysed to parent
drug in blood
Esters of erythromycin
Principal areas of Preformulations

123. Enhancementof Bioavailability
The dipalmitoyl gylcerolesterof NSAID naproxen – less
GI and high plasma conc.
Intraocular penetration of polar drugs– β blockers and
epinephrine– treatment of glaucoma– uselipophilic
carrier
Eg.:diacetate esterof nadolol is20 times more lipophilic
and 10 times more readilyabsorbed ocularly
The dipivalylesterof epinephrine– good ocular
penetrability (8-17times) in comparison to the parent drug

124. Enhancementof Bioavailability
Increasedbioavailability through increasedlipophilicity – Is
reduction in drug dosage
Eg.: bacampicillin – prodrug for ampicillin(1/3rd the
dose)
Bioavailabilityof topicallyapplied drug – depends on
lipid solubility
Skin penetrability of polar drugscanbeimproved by
esterification to form lipid soluble compound
Drugs with carboxylfunctions istheir esterfication
with oneof the hydroxyl groups of PG or glycerol
Penetration enhancer– PG or glycerol
Eg:glycerylester of naproxen

125. First Pass Metabolism
Corticosteroids – extensiveFPM
Use their ester or ether prodrugs
Eg.:triamcinolone acetonide
Propanolol – its hemisuccinateprodrug resistant to
esterasesof liver

126. Duration Of Action
Prolonged DOA:
Shorter half life:Frequent dosing required
Overcomebyuseof both controlled releaseand prodrug
approches
Rate of releaseof prodrug – Controlled release
Conversionof prodrug to drug- Controlled release
Eg:IM depot inj. Of lipophilic esterprodrugs of steroids
(testosterone cypionateand propionate,estradiol propionate)
Antipsychotics(fluphenazineenanthateand decanoate)
Pilocarpine – glaucoma(diesters of the drug)

127. Reduction of toxicity
Objective of drug design:highactivitywith low toxicity
Eg.:timolol and epinephrine
High dose– Poor penetration ,CV side effects
Lipophilic esters– Betterintraocular penetration and
reducesthe instilled doses– reducesadverse effects
Eg.:TI of alkylesterprodrug of timolol – improved
16times whilethat of dipivalylepinephrineor dipivefrin
(a diester of epinephrinewith pivalicacid) increased
10times
Improved biochemical(decreased metabolic rate in
ocular tissues) and chemical stability (resistance to
oxidation)

128. Site Specific Drug Delivery
SelectiveUptake systems
Redox systemfor drug deliveryto brain
Sitespecificdrug deliveryin cancer
Limitations of prodrug design :
Toxicity – maybedue to
Formation of an unexpectedmetabolite from total prodrug that
maybetoxic
Inert carrier generatedfollowingcleavageof prodrug mayalso
transform into atoxicmetabolite
During activation,consumptionof vitalcellconstitutent suchas
glutathione leadingto its depletion
Eg.: Prodrug Phenacetin – paracetamol – de-ethylation. Other
intermediates likep-phenetidine and n hydroxyphenacetinisalso
formed
p-phenetidine – further metabolizesto ppt
methemoglobinemia,hemolysis and renal toxicity

129. REFERENCES
The Theory and Practice of Industrial Pharmacy
ByLeon Lachman,H.ALieberman,JosephKanig,3rd
edition ,page: 184-195

130. REFERENCES
The Theory and Practice ofIndustrial
Pharmacy
By Leon Lachman, H.A Lieberman, Joseph
Kanig, 3rdedition ,page: 171-176
www.pharmacy.utah.edu/pharmaceutics/p
df/Preformulation.pdf

131. References
Biopharmaceutics andPharmacokinetics
A treatise – By D.M Brahmankar and Sunil
B.Jaiswal,Page :159-177

132. References
Lachman,Page:772-786