2. Content
Introduction
Definition
Factors to be considered before Preformulation
Objectives and goals
Outcomes
Tests involved in Preformulation
Solubility studies
Stability studies
Chemical characterization
2
3. Introduction
Preformulation is branch of Pharmaceutical science that utilizes
biopharmaceutical principles in the determination of physicochemical
properties of the drug substance.
Prior to the development of any dosage form new drug , it is essential that
certain fundamental physical & chemical properties of drug powder are
determined .
This information may dictate many of subsequent event & approaches in
formulation development.
This first learning phase is called as Preformulation.
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4. Definition
It is defined as phase of research and development in which investigation of
physico-chemical properties of the new drug compound that could affect drug
performance and development of an efficacious dosage form”.
Preformulation commences when a newly synthesized drug shows a sufficient
pharmacologic promise in animal model to warrant evaluation in man.
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5. Factors to be considered before Preformulation
Amount of drug available at site.
Physico-chemical properties of drug already known.
Therapeutic category and an anticipated dose of compound.
Information regarding formulation characteristics and its compatibility.
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6. Objectives and goals
To generate useful information to the formulator to design an optimum drug
delivery system.
To establish the necessary physicochemical parameters of new drug
substances.
To determine kinetic rate profile.
To establish physical characteristics.
To establish compatibility with common excipients.
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7. Outcomes
The expected outcomes are that the product:
Will deliver the drug to the site of action at the intended concentration.
Will meet product specifications, including limits for content of drug and
impurities, and suitable physicochemical tests such as dissolution rate, particle
size of suspensions etc.
Will be consistent from one dosage unit to another (e.g. tablet to tablet), from
batch to batch, and from one manufacturing site to another. That includes
consistent bioavailability.
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8. Will be chemically and physically stable for a suitable time period under
convenient storage conditions. That is it continues to meet specifications
Can be manufactured at a cost that is consistent with the price that will be
paid.
As far as is possible, will be acceptable to the patient in terms of convenience
and palatability.
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9. Tests involved in Preformulation
Pre-formulation
Analytical
Physical
properties
Chemical
properties
Pharmaceutical
properties
9
10. Solubility studies
Solubility can be defined as the amount of substance that passes into solution
in order to establish equilibrium at constant temperature and pressure to
produce a saturated solution.
Solubility studies is an important parameter in pre-formulation studies.
Solubility of the molecules in various solvents is determined as first step.
This information is useful in development of formulation.
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11. Importance of solubility
To determine the dissolution medium for carrying in vitro dissolution study.
To determine binder for granulation.
To determine the extent of absorption of drug in stomach and intestine.
For prediction of dosage form.
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12. SOLUBILITY ANALYSIS
Analytic method that are particularly useful for solubility measurement
include HPLC, UV spectroscopy, Fluorescence spectroscopy and Gas
chromatography.
Reverse phase HPLC offer accurate and efficient mean of collecting solubility
data of drug.
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14. AQUEOUS SOLUBILITY
There are two fundamental properties mandatory for a new compound.
INTRINSIC SOLUBILITY (CO) :-
S = So {1 + (K1 / [H+])} ------ for weak acids.
S = So {1 + ([H+] / K2)} ------ for weak bases.
where, S = Solubility at a given pH.
So = Intrinsic solubility of the neutral form.
K1 = Dissociation constant of weak acid.
K2 = Dissociation constant of weak base.
14
15. The intrinsic solubility should ideally be measured at two temperatures
(1) 4 °C To ensure physical and chemical stability.
(2) 37°C To support biopharmaceutical evaluation
Method to determine solubility
(1) Equilibrium solubility method
(2) Turbidometric solubility method
(3) Nephlometric solubility method
(4) Ultrafiltration LC/MS solubility method
(5) Direct solubility method
(6) NRTL – SAC method
(7) COSMO SAC method
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16. ionization constant:-
75 % of all drugs are weak bases,
20 % are weak acids and only,
5 % are nonionic amphoteric or alcohol.
Henderson-Hasselbalch equation:-
pH = pKa + log [ionized form] / [unionized form] --- for acids.
pH = pKa + log [unionized form] / [ionized form] --- for bases.
16
17. Uses of these equations:-
To determine pKa.
To predict solubility at any pH provided that Co & pKa are known.
To facilitate the selection of suitable salt forming compounds.
To predict the solubility & pH properties of the salts.
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18. SOLUBILIzaTion
Many different approaches have been developed to improve drug
solubility.
Micronization:-
E.g.. Griseofulvin shows increased solubility by reducing particle
size.
Change in pH:-
E.g.. Solubility of Nimesulide increases as pH is increased.
E.g.. Arginine increases solubility of coumarins.
E.g.. Etoposide formulation is difficult because of its poor solubility &
labile chemical stability so Etoposide loaded emulsion (ELE) is
formulated most stable at pH 4-5.
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19. 1919
Cosolvency:-
Addition of a water miscible solvent can often improve the
solubility of a weak electrolyte or non-polar compound in water by
altering the polarity of the solvent.
Limited choice due to possible toxicity & irritancy.
Ideally suitable : Dielectric constant (near to 80).
Water / ethanol : Most widely used system.
Solubilization by surfactant:-
E.g.. Gelucire 44/14 is a surface active excipient that can solubilize
poorly soluble drug.
E.g.. Anionic & cationic surfactants exhibited dramatically higher
solubilization for gliclazide, while nonionic surfactants showed
significantly lower solubilizing ability.
20. 2020
Complexation:-
E.g.. The complexation of iodine with 10-15% PVP can improve
aq. solubility of active agent.
Formation of Inclusion Compound:-
Enhanced solubility of oxicams through inclusion of β
cyclodextrin and its derivatives.
E.g.. The enhancement of solubilization increased 300 fold for
Nimodipine at a polymer conc. 10% by use of water soluble
dendrimer based on polyglycerol.
Use of Metastable polymorphs:-
Eg. B form of Chloramphenicol palmitate is more water
soluble than A & C forms.
21. 2121
PARTITION COEFFICIENT:-
When a solute is added to two immiscible liquids it will distribute
itself between the two phases in a fixed ratio, which is referred to as
partition or distribution coefficient.
Various organic solvents used in determination of partition
coefficient include Chloroform, ether, amyl acetate, etc.
In formulation development, the n-octanol/water partition
coefficient is commonly used.
P = (Concentration of drug in octanol) ---- For unionizable drugs.
(Concentration of drug in water)
P = (Concentration of drug in octanol) ---- For ionizable drugs.
(1-α)*(Conc. of drug in water)
where α = degree of ionization.
22. 2222
P > 1 Lipophilic drug.
P < 1 Hydrophilic drug.
Methods to determine P:-
Shake Flask Method.
Chromatographic Method (TLC, HPLC).
Counter Current & Filter Probe method.
Applications of P:-
Measure of lipophilic character of molecules.
Recovery of antibiotics from fermentation broth.
Extraction of drug from biological fluid
Absorption of drug from dosage forms.
Study of distribution of flavoring oil between oil & water in
emulsion.
23. 2323
THERMAL EFFECT:-
Effect of temperature on the solubility of drug can be
determined by measuring heat of solution. (∆Hs).
ln S = -∆Hs/R*T + C
where, S = Molar solubility at temperature T (ºK).
R = Gas constant.
Heat of solution represents the heat released or absorbed when a
mole of solute is dissolved in a large quantity of solvent.
Typical temp. range should include 5ºC, 25ºC, 37ºC & 50ºC.
Importance: Determination of temperature effect on
solubility helps in predicting storage condition & dosage
form designing.
24. 2424
COMMON ION EFFECT:-
To identify a common ion interaction the IDR of HCl salt
should be compared between
• Water & water containing 1.2% W/V NaCl.
• 0.05 M HCl & 0.9% NaCl in 0.05 M HCl.
Both saline media contains 0.2 M Cl־ which is typically
encountered in fluids in vivo.
DISSOLUTION
The absorption of solid drugs administered orally can be
understood by following flowchart.
Kd Ka
Dissolution Absorption
when Kd<<<<Ka, absorption is dissolution rate limited.
Solid drugs
in GI fluid
Solution
of drug in
GI fluid
Drug in
systemic
circulation
25. 2525
Dissolution rate can affect:-
• Onset of action
• Intensity of action.
• Duration of response.
• Control the overall Bioavailability of drug form.
Dissolution is to be considered of 2 types:
Intrinsic dissolution
Noyes-Whitney equation:
To predict if absorption would be dissolution rate limited or
not.
dC/dt = AD(Cs-C) / hv
Method to determine intrinsic dissolution:-
Rotating disk method or Wood’s apparatus:
For determination of dissolution from constant surface area.
26. Particulate dissolution
Determine the dissolution of solids at different surface area.
It is used to study the influence on dissolution of particle size, surface area
& mixing with excipients.
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27. STABILITY ANALYSIS
Development of a drug substance into a suitable dosage form requires the
preformulation stability studies as:
– Solid state stability.
– Solution state stability
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29. SOLID STATE STABILITY:-
• Solid state reactions are much slower & more difficult to interpret than
solution state reactions because of reduced no. of molecular contacts
between drug & excipient molecules & occurrence of multiple reactions
Techniques for solid state stability studies:
• Solid State NMR Spectroscopy. (SSNMR)
• Powder X-ray diffraction. (PXRD)
• Fourier Transform IR. (FTIR)
• Raman Spectroscopy.
• Differential Scanning Calorimetry. (DSC).
• Thermo gravimetric Analysis. (TGA).
• Dynamic Vapor Sorption. (DSV).
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30. SOLUTION STATE STABILITY:-
The primary objective is identification of conditions necessary to form a
stable solution.
These studies include the effects of
• pH.
• Oxygen.
• Light.
• Temperature.
• Ionic Strength.
• Cosolvent
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31. • If the results of this solution stability studies dictate the compound as
sufficiently stable, liquid formulation can be developed.
• E.g.: Aq. Solution for injection pH 3 containing Irinotecan HCl, phosphate
buffer & WFI was stably prepared by dissolving camptothecins without
resorting to heating in the course of production.
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32. 3232
Stress conditions usedin preformulation stability assessment:
TEST CONDITION
SOLID
Heat (°C) 4,20,30,40,40/75 % RH, 50 & 75.
Moisture uptake 30,45,60,75&90% RH at RT.
Physical stress Ball milling
AQUEOUS SOLUTION
pH 1,3,7,9 & 11 at RT & 37ºC.
Reflux in 1M HCl & 1M NaOH.
Light UV (254 & 366 nm) & Visible at RT.
Oxidation Sparing with oxygen at RT, UV may
accelerate breakdown.
33. 3333
CHEMICAL CHARACTERISTICS
OXIDATION
It is a very common pathway for drug degradation in both liquid &
solid formulation.
Oxidation occurs in two ways:-
1. Auto oxidation.
2. Free radical chain process.
Functional groups having high susceptibility
towards oxidation:-
• Alkenes.
• Substituted aromatic groups. (Toluene, phenols, anisole).
• Ethers.
• Thioethers.
• Amines.
34. 3434
AUTO OXIDATION FREE RADICAL SCAVENGER
• It is defined as a
reaction of any
material with
molecular oxygen
which produces free
radicals by homolytic
bond fission of a
covalent bond.
• These radicals are
highly unsaturated &
readily take electron
from other substance
causing oxidation.
1) Initiation
RH R• + H•
2) Propagation
R• + O2 RO2
•
RO2
• + RH ROOH + R•
3) Decomposition
ROOH RO• + OH•
4) Termination
RO2
• + X Inactive
product
RO2. + RO2 Inactive
product
OXIDATION
35. 3535
Factors affecting oxidation process:-
Oxygen concentration.
Light.
Heavy metals particularly those having two or more valence
state.
Hydrogen & Hydroxyl ion.
Temperature.
36. 3636
Prevention of oxidation:-
Reducing oxygen content.
Storage in a dark & cool condition.
Addition of chelating agent. [E.g.. EDTA, Citric acid, Tartaric acid].
Adjustment of pH.
Changing solvent. [E.g.. Aldehydes, ethers, ketones may influence
free radical reaction].
Addition of an antioxidant.
• Reducing agent.
• Chain inhibitors of radical induced decomposition
38. 3838
HYDROLYSIS
• It involves nucleophilic attack of labile groups.
• Eg. Lactam > Ester > Amide > Imide.
• When this attack is by a solvent other than water then
• it is known as solvolysis.
• It generally follows 2nd order kinetics as there are 2 reacting species,
water and API.
• In aqueous solution, water is in excess, the reaction is 1st order.
Conditions that catalyze the breakdown:-
• Presence of hydroxyl ion.
• Presence of hydride ion.
• Presence of divalent ion.
• Heat.
• Light.
• Ionic hydrolysis.
• Solution polarity & ionic strength.
• High drug concentration.
39. 3939
Prevention of hydrolysis:-
pH adjustment.
• Formulate the drug solution close to its pH of optimum stability.
• Addition of water miscible solvent in formulation.
• Optimum buffer concentration to suppress ionization.
Addition of surfactant:
• Nonionic, cationic & anionic surfactant stabilizes the drug
against base catalysis.
Salts & esters: E.g.. Phosphate ester of Clindamycin.
The solubility of p’ceuticals undergoing ester hydrolysis can be
reduced by forming less soluble salts.
Store with desiccants.
By use of complexing agent.
40. Photolysis
Mechanism of decomposition:-
Electronic configuration of drug overlaps with spectrum
of sunlight or any artificial light, & thereby energy is
absorbed by electron & it goes to the excited state.
They are unstable & release the acquired energy & come
to the ground state & decompose the drug.
4040
41. 4141
Photosensitization means molecule or excipient which absorbs
energy but do not participate themselves directly in the reaction but
pass the energy to other that will cause cellular damage by inducing
radical formation.
Photosensitizer
Energy transfer Electron transfer
Convert oxygen
from its ground state
to singlet excited
state.
Generate superoxide
molecule, which is an
anion radical & acts as a
powerful oxidizing
agent.
42. 4242
PHOTODECOMPOSITIONPATHWAYS
N-Dealkylation:
Eg. Diphenhydramine, Chloroquine, Methotrexate.
Dehalogenation:
Eg. Chlorpropamide, Furosemide.
Dehydrogenation of Ca++ channel blocker.
Eg. Solution of Nifedipine → Nitrosophenylpyridine
(with loss of water).
Rapidly yellow color
Brown.
43. 4343
Decarboxylation in anti-inflammatory agents.
E.g.. Naproxen, Flurbiprofen, Benzoxaprofen.
Oxidation.
E.g.. Chlorpromazine & other phenothiazine give N- & S-
oxides in the presence of sunlight.
Isomerization & cyclization.
E.g.. Noradrenaline, Doxepine.
Rearrangement.
E.g.. Metronidazole → Oxidiazine → Yellow color.
44. 4444
• Aq. solution of Lincomycin was irradiated with UV light in
homogenous & heterogeneous systems. Lincomycin
disappeared in both systems but the presence of TiO2
noticeably accelerated the degradation of antibiotic in
comparison with direct pyrolysis.
• The degradation pathways involved S- & N- demethylation &
propyl dealkylation.
• The photodegradation behavior of bisphenol C studied in
monochromatic UV irradiation (λ= 254 nm) indicated that
phtotodegradation reaction rate constant of bisphenol C in aq.
soln. with β- cyclodextrin is higher than that without β-
cyclodextrin, mainly due to lower bond energy between some
atoms in bisphenol C molecule after inclusion interaction with
β- cyclodextrin.
45. 4545
Preventionof Photodecomposition:-
Suitable packing.
Eg. Yellow-green glass gives the best protection in U.V. region
while Amber confers considerable protection against U.V. radiation
but little from I.R.
Use of Anti-oxidant.
Eg. Photodegradation of Sulphacetamide solution may be
inhibited by an antioxidant such as sodium thiosulfate or
sodium metabisulphate.
Protection of drug from light.
Eg. Nifedipine is manufactured under Na light.
46. 4646
Avoiding sunbath.
E.g.. Sparfloxacin.
Photostabilizer [Light absorber].
Colorant Curcumin, Azorubine.
Pigments Iron oxide, Titanium dioxide.
Coating:
Pigments like TiO2(IN NIFEDIPINE) / ZnO.
E.g.. Photostabilization of Sulphasomidine Tab. by film
coating containing U.V. absorber (Oxybenzone) to protect
color & photolytic degradation.
47. 4747
RACEMIZATION
The interconversion from one isomer to another can lead to
different P’cokinetic properties (ADME) as well as different
P’cological & toxicological effect.
Eg. l-epinephrine is 15 to 20 times more active than d-form,
while activity of racemic mixture is just one half of the l-form.
It follows first order kinetics.
It depends on temperature, solvent, catalyst & presence or
absence of light.
48. 4848
POLYMERIZATION
It is a continuous reaction between molecules.
More than one monomer reacts to form a polymer.
Eg. Darkening of glucose solution is attributed to
polymerization of breakdown product [5- (hydroxyl methyl)
furfural].
Eg. Shellac on aging undergoes polymerization & hence
prolongs disintegration time &dissolution time.
49. 4949
ISOMERIZATION
It is the process involving change of one structure to another
having same empirical formula but different properties in one
or more respects.
Its occurrence is rare.
Examples:-
Tetracycline & its derivatives, can undergo reversible
isomerization at pH range 2-6.
Trans-cis isomerization of Amphotericin B.
Isomerization of tetrahydrouridine.
50. 5050
DECARBOXYLATION
Evolution of CO2 gas from –COOH group containing drugs.
Eg. Solid PAS undergoes decarboxylation to m- aminophenol
& Carbondioxide.
ENZYME DECOMPOSITION
Chemical degradation due to enzymes induced by drug results
into decomposition.
Remedy:
Use of buccal tab.
Use of pro-drug. (L-dopa).
Improvement in physico chemical properties has been achieved
by structural optimization or prodrug approach – Enhancement
of ocular penetration when given orally.(ORAL DRUG
DELIVERY SYSTEM).
51. CONCLUSION
Preformulation studies on a new drug molecule provide useful information for
subsequent formulation of a Physico-chemically stable and
Biopharmaceutically suitable dosage form. ‰Thorough Preformulation work is
the foundation of developing efficacious and economical formulations.
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52. REFERENCE
1. Leon lachman, Herbert liberman, Joseph L. kanig , The theory and practice
of industrial pharmacy , 3rd Edition , Indian Edition, pp 171-194, Varghese
publishing house , Mumbai .
2. Patrick J. Sinco, Martin’s Physical pharmacy & Pharmaceutical science, 5th
edition , pp 547-550, Lippincott williams & wilkins, New York.
3. Garima V, Manoj M , “Pharmaceutical Preformulation Studies in
Formulation and Development of New Dosage Form: A Review.”, Int J. of
Pharma Research & Review, 2016, 5 , 12-20.
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