Pharmaceutical knowledge skills topic for comprehensive patientcare service provision

1. Preformulation Characteristics of
Pharmaceutical Product Systems

2. Course Content
 Introduction of Preformulation subject
 Preformulation Characteristics
 Principle Areas of Preformulation

3. 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.

4. 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.

5. Drug Development Cycle

6. 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

7. 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

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

9. 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

10. 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

11. 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?

12. 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

13. Any Questions

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

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

16. Principal areas of
Pre-formulations
 Bulk Characterization
 Solubility Analysis
 Stability Analysis

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

18. 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

19. 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

20. Crystallinity and polymorphism
 Changes in internal structure for a compound – Alter
change in the crystal habit.
 Characterisation Involves –
 Verifying the solid is the expected chemical compound
 Characterization the internal structure
 Describing the habit of the crystal
Prismatic
Bladed

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

23. Crystallinity and polymorphism
 Crystals
 Repetitious spacing of constituent atoms or molecules
in 3 dimensional array
 Amorphous
 Have atoms or molecules randomly placed, prepared by
Rapid precipitation
Lyophilization
Rapid cooling of liquid melts
 Amorphous – Higher thermodynamic energy,
solubilites and dissolutions is also high.
 Upon storage – Tends to revert more stable forms
 Disadv.: Thermodynamic instability

24. Crystallinity and polymorphism
 Crystalline –
 Nonstoichiometric adducts – entrapped solvents within
crystals. Eg.: Inclusions
 Undesirable, Lack of reproducibility – Avoided
 Stoichiometric adducts – As a solvate, is a molecular
complex that has incorporated the crystalline solvent
molecules into specific sites within crystal lattice
 Eg.: water ( hydrate- monohydrate)
 Aq. Solubilities, Eg Ampicillin
 Dissolution - bioavailability

25. Crystallinity
Conversion of an anhydrous compound to a hydrate
within the dosage form may reduce the dissolution
rate & extent of drug absorption.

26. 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

27. 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

28. 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 and acetazolamine,Sulfur

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

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

31. 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.

32. 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

34. 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

35. Scanning electron microscopy
(SEM)

36. 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

37. 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.

38. Fine Particle Characterization
Bulk flow, formulation homogeneity and surface area
controlled processes such as dissolution.
 Microscopy
 Coulter counter
 Sieve method
 BET method (Surface area)
 SEM method

39. 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

40. BET method
 Braunner, Emmett and Teller method
 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

41. Bulk Density
 Bulk density :
 Varies with Method of crystallization, milling or
formulation
 High dose – Size of capsules
 Low dose - homogeneity
 Drug and excipients
 Tapped density
 True density

42. Powder Flow properties
Powder Flow properties: Free flowing or
cohesive
Factors affecting are-
particle size, density, shape, moisture
content, electrostatic charge
-Flow rates (g/sec)
-Compressibility Index
-Angle of repose

43. Way to improve flow properties
-Granulation
-Slugging/ compaction
-Glident

44. Any Questions

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

46. Solubility Analysis
 What is solubility??
 Factors affecting solubility
 Saturation solubility
 What is Dissolution??

47. Very soluble less than 1 part
Freely soluble from 1 to 10 parts
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

48. Solubility Analysis
 Solubility study done in various solvents
-Aqueous solvent
- water, buffers
-Nonaqueous solvents
- Organic solvents
- Glycerol, PEG

49. Solubility Analysis
 Focus on drug-solvent system that could
occur during the delivery of the drug
candidate
 Provides basis for formulation work.
 Determination of
 pKa
 Temperature dependence
 pH solubility profile
 Solubility products
 Solubilization mechanisms
 Rate of dissolution

50. 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

51. pKa Determination
 Dissociation constant is capability of drug
to ionize within pH range of 1 to 10
 Solubility & absorption altered
 Henderson-Hasselbalch equation
 Acidic compounds
 Basic Compounds

52. 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

53. 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

54. Effect of Temperature
 Solution Process
 Endothermic
 Heat of solution is positive
 Exothermic
 Heat of solution is negative ( lithium salts)
 Non-electrolytes & ionized forms ΔH between 4 to 8 kcal/mol
 Salt forms of drugs -2 to 2 kcal/mole (less sensitive to temp.)
 Effect solution dosage form design & storage condition.
 Solvent systems including co-solvents.
 Micelles
 Complexation

55.  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
 ΔHs obtained 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

56. 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

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

58. pH Solubility Profile & Common Ion
Effects
 Solubility of an acidic or basic drug
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.

59. 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.

60. 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

61. 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.

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

63. Any Questions

64. Principal areas of Preformulations
 Stability Analysis
 Stability in toxicology formulations
 Solubility stability
pH rate profile
 Solid state stability
Bulk stability
Compatibility

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

66. Stability Analysis
 Preformulation studies give first quantitative
assessment of chemical stability of a new drug.
Solution State Solid State
Handling, formulation, storage and administration of a
drug candidate
 Test protocols & experimental methods
 Assay – intact drug and degraded product
Evaluation – HPLC, Gas Chromatography
Degradation study

67. Stability in toxicology formulations
 Since toxicological studies typically commence early in drug
development, it is often advisable to evaluate samples of
toxicology preparations for Stability and potential
homogeneity problems
 Drug administered – Feed or oral gavage of solution or
suspension of drug in an aqueous vehicle
 Minerals, vitamins, enzymes , a multitude of functional
groups present in feed – reduces shelf life of drug
 Fresh sample of feed to be used
 Solution or suspension – Checked for ease of manufacture
 Stored in a flame sealed ampoules at various temperatures
 Occasionaly shaking – Dispersability

68. Solution Stability
 Aim-Identification of conditions necessary to form a stable
solution
 Study Includes – effects of pH, Ionic strength, Co-solvent, light ,
temperature and oxygen
 Probing experiments at extremes conditions of pH and
temperature (0.01N HCl , water ,0.01N, NaOH all at 90°C).
 Assay specificity and Maximum rates of degradation
 Complete pH rate profile – pH of max stability.
 Aq. Buffers are used to provide wide range with constant levels of
drug, co solvent and ionic strength
 Compatible with physiological media
 Eg.: Ionic strength ( µ) of 0.9% NaCl is 0.15
 Equation: µ = ½ ∑miZi
2
 mi = molar conc. of the ion, with valence Zi

69. Solution Stability
 Procedure-
Stability solutions : Flint glass ampoules, flame sealed –
prevent evaporation, Stored at temperature not exceeding
its Boiling Point (if organic co-solvents are used).
 Varied temp- Activation energy
 Light stability – protective packing
 Amber – yellow –green glass containers
 Wrapped in aluminium foil or cardboard packages
 Potential for oxidation:
 Excessive headspace of O2
 Excessive headspace with inert gas
 Inorganic antioxidant – Sodium metabisulfite
 Organic antioxidant – Butylated hydroxytoluene BHT

70. Solution Stability
 pH rate profile
 Stability data at each pH and temperature
 Analyzed kinetically – apparent decay constant
 Arrhenius plot – log of apaprent decay rate constant Vs
reciprocal of absolute temperature
 Energy of activation

71. Solid state stability
Aim: Identifications of stable storage conditions for
drug in the solid state and identification of
compatible excipients for a formulations.
 Affected by change in purity and crystallinity
 Initial bulk lots and newer lots– to be studied
 Solid state is slower and difficult to interpret than solution
state
 TLC, UV-Vis, fluorescence
 Polymorphic changes – DSC, IR or appearance changes like
oxidation – surface discoloration
Procedure: Open screw cap vials – Exposed to various
conditions Temp., Humidity and light upto 12weeks
 Samples – 5-10mg(HPLC), 10-50mg for DSC

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

73. Elevated temperature studies
 The elevated temperatures commonly used are 40, 50, and
60 degree centigrade with ambient humidity.
 The samples stored at highest temperature are observed
weekly for physical and chemical changes and compared to
an appropriate control .
 If a substantial change is seen, samples stored at lower
temperature are examined .
 If no changes is seen after 30 days at 60°C , the stability
prognosis is excellent.

74. Stability under high humidity conditions
 Solid drug samples can be exposed to different
relative humidity conditions by keeping them in
laboratory desiccators containing saturated
solutions of various salts.
 The closed desiccators in turn are kept in oven to
provide constant 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 aqueous solvent be used during formulation.

75. Photolytic stability
 Many drugs fade or dorpen on exposure light.
 Increased Impurity level
 Samples should be exposed to light providing an overall
illumination of not less than 1.2 million lux hours and an
integrated near ultraviolet energy of not less than 200 watt
hours/square meter
 If protected samples (e.g., wrapped in aluminum foil) are
used as dark controls to evaluate the contribution of
thermally induced change to the total observed change,
these should be placed alongside the authentic sample.
 Resulting data may be useful in determining if an amber
colored container is required or if color masking bye
should be used in the formulation

76. Stability to Oxidation
 Drug’s sensitivity to oxidation can be examined by
exposing it to atmosphere of high oxygen tension.
 Usually a 40% oxygen atmosphere allows for rapid
evaluation.
 Samples are kept in desiccators equipped with three-
way stop cocks, which are alternatively evacuated and
flooded with desired atmosphere.
 The process is repeated 3 or 4 times to ensure 100%
desired atmosphere.
 Results may be useful in predicting if an antioxidant is
required in the formulation or if the final product
should be packaged under inert atmospheric conditions.

77. Compatibility studies
 The knowledge of drug excipients interaction is
useful for the formulation to select appropriate
excipients.
 The described preformulation screening of drug
excipients interaction requires only 5mg of drug in
a 50% mixture with the excipients to maximize the
likelihood of obscuring an interaction .
 Mixtures should be examined for physicochemical
properties like appearance, Assay and degradation
products.

78. Formulation Recommendation
 Upon the completion of preformulation evaluation
of a new drug candidate, it is recommended that a
comprehensive report to be prepared highlighting
the pharmaceutical problems associated with this
molecule.
 This report should conclude with recommendations
for developing phase I formulations.
 These reports are extremely important in preparing
regulatory documents & aid in developing
subsequent drug candidates.

79. Any Questions

80. 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.

81. Study of chemical properties of drugs like
 Hydrolysis
 Oxidation – Reduction
 Photolysis
 Racemisation
 Polymerization
Mechanisms of degradation and their influence on
formulation and stability of products

82. OBJECTIVE
 Initial investigation on chemical properties
 Knowledge about the chemical and physical
stability of a candidate 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 experiments need to be performed

83. Hydrolysis: (drug) molecules interact with water molecule
to yield breakdown product.
 Susceptible to the hydrolytic process: esters, substituted
amides, lactones, and lactams.
Eg: Anestheics, antibiotics , vitamins and barbiturates
1. Ester hydrolysis:
 Ester Acid + Alcohol (involves rupture of a
covalent linkage between a carbon atom and an oxygen
atom).
 Catalysts – polar nature such as mineral acids, alkalies or
certain enzymes – capable of supplying H+ and OH- ions
 Acid or alkali catalysed hydrolysis
Degradation Pathway
Hydrolysis

84. Ester Hydrolysis

86. Kinetic study of hydrolysis of Aspirin was done
in various buffer solutions. It was observed that Aspirin is
most stable at 2.4, at pH 5 to 7 degradation is pH independent
and above pH 10 stability decreases with increase in pH.

87. Factors to be considered in Hydrolysis
 pH
 Type of solvent : solvent lower dielectric 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 of benzocaine
 Modification of chemical structure
 Salts and esters

88. Amide hydrolysis
 Hydrolytic reaction results :
 Amide Acid +Amine
 Eg.: Chloramphenicol
 Niacinamides
 Ring alterations: hydrolysis proceed as a result of
ring cleavage.
 Eg. Pilocarpine

89. Oxidation - reduction
 Second most common way.
Eg.: steroids, vitamins ,antibiotics etc
 Mediated by free radicals or by molecular oxygen
 Complex oxidative processes
 Sensitive towards trace metal and other impurities
 Redox reactions involve either transfer of oxygen
or hydrogen atoms or transfer of electrons

90. Oxidation - reduction
 Oxidation – presence of oxygen
 Initiated by heat ,light or trace metal ions that
produce organic free radicals
 These radicals propagate the oxidation reaction ,
which proceeds until inhibitors destroy the
radicals or until side reactions eventually break
the chain
 Eg. Dopamine

91. Oxidation - reduction
 Substance is oxidized when :
 If electrons are removed from it
 Gains electronegative atoms or radicals or loses
electropositive atoms or radicals
 Addition of oxygen and removal of hydrogen
 Most common : autoxidation (free radical chain
process)
 Involves homolytic bond fission of a covalent bond
– each atom retains one of the electrons of original
covalent bond:

92. Autoxidation
 Initiation: RH R. + H.
 Propagation:
 R. + O 2 RO 2
 RO 2. + RH ROOH + R.
 Hydroperoxide decomposition
 ROOH RO. + .OH
 Termination
 RO2. +X Inactive products
 (X converts to peroxides group)
 RO2 +RO2 Inactive products
 Rate of prednisolone : presence of aerobic and anaerobic
conditions
 Rancidity – oils and fats
 Oxygen content and Antioxidants
Light, heat
Activation

93. Photolysis
 Photochemical
 Photosensitizer
 UV- violet portions – more active ( shortet
wavelength ,more energy)

94. Racemization
 Racemization – compound changes optical activity
without changing the chemical composition.
 Levo and dextro form
 Eg: l-adrenaline is 15-20times more active than
dextro form
 Racemic mixture
 Stability and therapeutic activity

95.  Kinetics of degradation:
K = rate of reaction
Drug – Product
Zero ,first , second order reactions, half life etc.
Effect of temperature : logk = log A – Ea/2.303RT
Depends on functional group of assymetrical carbon
atom,aromatic grp tends to accelerate racemization

96. Any Questions

97. Prodrugs
 Study of prodrugs in solving problems related to
Stability,
Bioavailability and
Elegancy of formulation
Principal areas of Preformulations

98. Prodrugs- Intoduction
 Drugs – Undesirable physicochemical and
biological properties
 How do one improve therapeutic efficacy?
 Biological, Physical and Chemical means
 Biological approach – Alters the ROA – may or
may not be acceptable by the patient
 Physical approach – Modify the design of the
dosage form Eg.: CDDS
 Chemical Approach – Best to enhance the drug
selectivity by minimizing the toxicity

99. Prodrug
 3 Chemical means – To optimize the drug
therapeutics
1. Design and development of new drugs with
desirable features
 Screening of chemicals for biological activity-
Clinically useful
2. Design of hard and soft drugs with desirable
characterisitcs
3. Design of prodrugs

100. Prodrug
 Hard drugs :Resistant to biotransformation - Long
biological half life, no toxic metabolite formation.
Disadv.: Accumulation
 Soft drugs: A biologically active drug compound i.e
biotransformed in vivo in a rapid and predictable
manner into non- toxic moieties. Relatively inert
metabolites
Disadv.: Short Duration Of Action
Ex. Insulin, adrenaline
Replacement of alkyl chain of drug – ester group –
readily hydrolysed in vivo

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

102. Carrier linked prodrugs
 Simple prodrugs
 Are ones where the active drug is covalently
linked to an inert carrier or transport moiety
 Esters or amides
 Greatly modified lipophilicity due to the
attached carrier
 Active drug released by hydrolytic cleavage
either chemically or enzymatically

103. Carrier linked prodrugs

104. Bioprecursors
 Known as Metabolic precursors
 Are inert molecules obtained by chemical
modifications of active drug but do not
contain a carrier
 Moiety has same lipophilicity as the parent
drug
 Bioactivated by redox biotransformation only
enzymatically
 Eg.: Arylacetic acid NSAID – fenbufen from
aroylpropionic acid precursors.

105. Bioprecursors

106. Pro-Prodrug
Few cases of carrier type prodrugs to be formulated as
ophthalmic, parenteral or oral liquid preparations, the
conversion to active drug –- Chemically ( non
enzymatically) triggered by change in pH –- Stability
problems
Overcome by :
 Double prodrug or pro-prodrug concept
 Further derivatized in a fashion – Only
enzymatically conversion of prodrug is possible
before the latter can cleave to release the active drug
 Eg.: diesters of pilocarpic acid

107. Mutual Prodrug
 In contrast to simple prodrugs where the carrier
used is biologically inert,
 Prodrug comprises of 2 pharmacological active
agents coupled together to form a single molecule
that each acts as carrier for the other
 Prodrugs of two active compounds are called as
mutual prodrugs
 Eg.: Benorylate : For NSAID’s of aspirin and
paracetamol

108. Examples of Prodrug
 Aspirin – Produg of salicylic acid- decrease
GI irritation
 Hexamine – Excreted in urine is converted to
formaldehyde in the acidic urine pH -
Urinary tract antibacterial

109. Ideal characteristics of Prodrug
 Shouldn’t have intrinsic pharmacological
activity- Inert
 Rapidly transform, chemically or enzymatically
into the active form where desired
 The metabolic fragments, apart from the active
drug should be nontoxic

110. Applications - Prodrug
 Pharmaceutical Applications:
 Improvement of taste
 Improvement of odor
 Change of physical form for preparation of solid
dosage forms
 Reduction of GI irritation
 Reduction of pain on injection
 Enhancement of drug solubility and dissolution
rate
 Enhancement of chemical stability of drug

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

112. Any Questions

113. Improvement of taste
 Poor patient compliances
 Bitterness, acidity etc
 Two approaches :Overcome taste
 Reduction of drug solubility in saliva
 To lower the affinity of drug towards taste
receptors
 Eg.: Chloramphenicol – Palminate ester
Principal areas of Preformulations

114. Improvement of odor
 Depends upon its vapor pressure (BP)
 High v.p has low b.p = Strong odor
Eg.: Ethyl mercaptan – foul smell at b.p
35°C
Used in treatment of leprosy,is converted to
phthalate ester (diethyldithio-isophthalate)
higher b.p and is odorless

115. Change of Physical form of the drug
 Liquid form – unsuitable for formulation as tablet
if dose is high
 Conversion of such liquid drug into solid prodrugs
- formation of symmetrical molecules – Higher
tendency to crystallize
 Eg. Trichloroethanol converted to
p-acetamidobenzoic acid ester

116. Reduction of GI irritation
 Irritation and damage to gastric mucosa
 Direct contact
 Increased stimulation of acid secretion
 Through interference with the protective mucosal
layer
Eg.: NSAID’s ,especially salicylates
Lowers the gastric pH and induces or aggravates
ulceration
Eg: Salicylic acid – Aspirin

117. Reduction of pain or injection
 IM injection – Painful when drug precipitates
or penetrates into the surrounding cells or
when the solution is strongly acidic , alkaline
or alcoholic
 Eg.1: Low aq. solubility of clindamycin HCl
Overcome by more water soluble prodrug
such as 2`-phosphate ester of clindamycin

118. Enhancement of solubility and
dissolution rate
 Hydrophilicity of drug:
 When dissolution is rate limiting step in absorption of
poorly aq.soluble agents or when parenteral or
ophthalmic formulations
Hydrophilic or water soluble drug are desired
 Eg: Drugs – OH group can be converted into their
hydrophilic forms by use of half esters such as
hemisuccinates, hemi glutarates etc
 Other half of these acidic carriers can form Na, K or
amine salts – renders the moiety water soluble

119. Enhancement of solubility and
dissolution rate
 For alcoholic or phenolic drugs :
Steroidal drugs like cortisol. prednisolone ,
dexamethsone, the sodium succinate salts have
poor stability and hence phosphate esters are
preferred
Eg1: Chloramphenicol – Sodium succinate
ester
Eg2: Tetracycline – Tetralysine
Eg3: Diazepam – L- lysine ester

120. Enhancement of chemical stability
 A drug may destabilize - shelf life or GIT Orally
 Shelf life stability- IV
 Conventional approach – Lyophilize such solutions into
powder which is reconstituted before use
 Improves stability
 Antineoplastic drug: azacytidine
 Aq.solution – hydrolyzed but bisulfite prodrug is stable to
degradation at acidic pH and more water soluble than the
parent drug
 Conversion at physiologic pH 7.4
 Cefamandole – nafate ester prodrug – improved shelf life(
Reconstitution from dry powder)

121. Prodrug stability
 Pencillins – More susceptible to hydrolysis and
destabilization in gastric acid
 Carbenicillin – cannot be administered orally
 Its ester prodrug carindacillin (α indanol ester) and
carfecillin (α phenyl ester – more stable
 At pH 7.0 hydrolysis releases the active drug and
absorbed
 Erythromycin – stearate( ethyl succinate and estolate )

122. Any Questions

123. Enhancement of Bioavailability
 Most drugs – Passive diffusion – 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

124. Enhancement of Bioavailability
 The dipalmitoyl gylcerol ester of NSAID naproxen – less
GI and high plasma conc.
 Intraocular penetration of polar drugs – β blockers and
epinephrine – treatment of glaucoma – use lipophilic
carrier
 Eg.: diacetate ester of nadolol is 20 times more lipophilic
and 10 times more readily absorbed ocularly
 The dipivalyl ester of epinephrine – good ocular
penetrability (8-17times) in comparison to the parent drug

125. Enhancement of Bioavailability
 Increased bioavailability through increased lipophilicity – Is
reduction in drug dosage
 Eg.: bacampicillin – prodrug for ampicillin (1/3rd the
dose)
 Bioavailability of topically applied drug – depends on
lipid solubility
 Skin penetrability of polar drugs can be improved by
esterification to form lipid soluble compound
Drugs with carboxyl functions is their esterfication
with one of the hydroxyl groups of PG or glycerol
Penetration enhancer – PG or glycerol
Eg: glyceryl ester of naproxen

126. First Pass Metabolism
 Corticosteroids – extensive FPM
 Use their ester or ether prodrugs
 Eg.: triamcinolone acetonide
 Propanolol – its hemisuccinate prodrug resistant to
esterases of liver

127. Duration Of Action
 Prolonged DOA:
 Shorter half life: Frequent dosing required
 Overcome by use of both controlled release and prodrug
approches
 Rate of release of prodrug – Controlled release
 Conversion of prodrug to drug- Controlled release
 Eg: IM depot inj. Of lipophilic ester prodrugs of steroids
(testosterone cypionate and propionate,estradiol propionate)
 Antipsychotics (fluphenazine enanthate and decanoate)
 Pilocarpine – glaucoma( diesters of the drug)

128. Reduction of toxicity
 Objective of drug design : high activity with low toxicity
 Eg.: timolol and epinephrine
 High dose – Poor penetration , CV side effects
 Lipophilic esters – Better intraocular penetration and
reduces the instilled doses – reduces adverse effects
 Eg.: TI of alkyl ester prodrug of timolol – improved
16times while that of dipivalyl epinephrine or dipivefrin
(a diester of epinephrine with pivalic acid) increased
10times
 Improved biochemical(decreased metabolic rate in
ocular tissues) and chemical stability (resistance to
oxidation)

129. Site Specific Drug Delivery
 Selective Uptake systems
 Redox system for drug delivery to brain
 Site specific drug delivery in cancer
 Limitations of prodrug design :
 Toxicity – may be due to
 Formation of an unexpected metabolite from total prodrug that
may be toxic
 Inert carrier generated following cleavage of prodrug may also
transform into a toxic metabolite
 During activation, consumption of vital cell constitutent such as
glutathione leading to its depletion
 Eg.: Prodrug Phenacetin – paracetamol – de-ethylation. Other
intermediates like p-phenetidine and n hydroxy phenacetin is also
formed
 p-phenetidine – further metabolizes to ppt
methemoglobinemia,hemolysis and renal toxicity

130. REFERENCES
 Pharmaceutical Preformulation by J.T.Cartensen published by Technomic
publishing Co., page no:- 1-6, 211-212.
 Ansel’s pharmaceutical Dosage forms & Drug delivery systems, 8th edition by Loyd
V. Allen, Nicholas G.popovich, Howard C. Ansel, publised by B.I.Publication pvt.
Ltd., page no:- 187-193,42 & 43,126-133.
 Textbook of physical pharmaceutics by C.V.S. Subrahmanyam, published by
Vallabh Prakashan, page no:- 182-208, 222-226.
 The theory & practice of industrial pharmacy by Leon Lachman, Herbert A.
Lieberman, Joseph L. Kenig, 3rd edition, published by Varghese Publishing house,
page no:- 171-184.
 Martin’s Physical pharmacy & Pharmaceutical science, 5th edition by Patrick J.
Sinco, Published by Lippincott Williams & Wilkins, page no:- 547-550.
 Pharmaceutical dosage forms : Tablet volume1, edited by Herbert A. Lieberman &
Leon Lachman, published by Marcel Dekker, page no:- 1-10.
 Biopharmaceutics and Pharmacokinetics , By D.M Brahmankar and Sunil
B.Jaiswal,Page :159-177
 Lachman , Page: 772-786
 www.pharmacy.utah.edu/pharmaceutics/pdf/Preformulation.pdf

131. Any Questions or Additions

133. Study Questions
 Define the following generic terms of pharmacy:
 [Preformulation, Formulation, Purity, solubilization, dissolution, ionization,
partition, agitation, complexation, surfactant, colour, odour, suspendibility,
penetrability, solubilty, compressibility, flowability, compatibility, disability,
permeability, micelle, hydotrophy, hypotrophy, surfactant, glidant, colorant,
disintegrant, lubricant, oxidant, diluent, humectant, cosolvancy, Crystallinity,
Polymorphism, Hygroscopicity, excipient, binders, fillers, abrasion, friability,
disintegrant, Adhesives,, Antiadherent, Flavor, Sweetener, Dosage, Toxicology,
deficiency, synthesis, crystallization, bioavailability, solubility, solubilization, dissolution,
stability, ionization, absorption, adsorption, metabolism, induction, Crystallinity,
polymorphism, Hygroscopicity, polymorphism, diffraction, hygroscopicity,
oxidation, reduction, hydrolysis, photolysis, racemization, bioprecursor,
prodrug, Medication, Compliance, Apothecary, Pharmaceutical compounding,
Millennium, Symptoms, Renaissance, Dosages, Storage, Pharmacopeia, Pharmacology,
Pharmaceutics, Pharmacokinetics, Therapeutics, Pathophysiology, Evolution, Nutrition,
Antibiotics, Chemotherapy, Pain management, Semiotician, Physician, Pharmacist,
Diagnosis, Mutual respect, Honesty/ Authenticity, Open Communication, Cooperation,
Collaboration, Empathy, Sensitivity, Promotion, Competence, Assurance, Confidence, etc]

134. Study Questions
 Respond to the following questions:
 Describe the pre-formulation consideration illustrating the term pharmaceutical
compounding
 Describe the formulation consideration illustrating the term pharmaceutical compounding
 Describe the generic pharmaceutical formulation consideration
 What constitutes the preliminary evaluation process in terms of pharmaceutical
manufacturing
 Describe the different types of Organoleptic Properties of Pharmaceutical Powders
considered during pharmaceutical product making
 Describe the different methods considered in the determination of particle sizes of
pharmaceutical particles
 Describe the different properties and habits of pharmaceutical materials in their powder
form flow
 Describe the different properties and habits of pharmaceutical materials in their fluid forms
 Describe the term crystallinity in terms of the shapes of the pharmaceutical crystals and
applications in pharmaceutical processing outcomes
 State and explain the Preformulation characteristics for pharmaceutical formulated products
 State and describe the principle areas of Preformulation
 State and explain the essential considerations in Preformulation process
 Explain in details the process of Preformulation and its role in integrity of the pharmaceutical product
output
 State and explain the critical components of Preformulation considerations

135. Study Questions
 Group work discussional questions for Journal Club
Meetings:
 Describe the pre-formulation consideration illustrating the
term pharmaceutical manufacturing
 Describe the formulation consideration illustrating the term
pharmaceutical manufacturing
 Describe the generic pharmaceutical formulation
consideration illustrating the term manufacturing
 State and explain the Preformulation characteristics for
pharmaceutical formulated products
 State and describe the principal areas of Preformulation
 State and explain the essential considerations in Preformulation
process
 Explain in details the process of Preformulation and its role in
integrity of the pharmaceutical product output
 State and explain the critical components of Preformulation
considerations