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on
Physicochemical factors
Under
Preformulation Study
What it is?
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DIRECT BENEFITS
Gives direction for development of
formulation in choice of dosage
form,excipients,composition,physical
structure.
Determine physical
If poor bioavailability test results due to
property of the new API.
solubility, pKa, P, etc. make new salt or ester
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Methods for determination of
Physicochemical properties
According to USFDA it can be characterized
as:-
1) Aqueous Solubility.
a. Intrinsic solubility.
b. Ionization constant.
2) Solubilization.
3) Partition Coefficient.
4) Thermal effect.
5) Common ion effect.
6) Dissolution.
C. STABILITY ANALYSIS
1) Solid State Stability.
2) Solution State Stability.
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II. CHEMICAL CHARACTERISTIC
1) Oxidation.
2) Hydrolysis.
3) Photolysis.
4) Racemization.
5) Polymerization.
6) Isomerization.
7) Decarboxylation.
8) Enzyme Decomposition.
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AQUEOUS SOLUBILITY:-
There are two fundamental properties mandatory for a new
compound.
Contd 9 9
The intrinsic solubility should ideally be measured at
two temperatures
(1) 4 C To ensure physical and chemical stability.
(2) 37C To support biopharmaceutical evaluation.
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(B) Ionization constant (pKa):-
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.
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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Methods to determine pKa:-
Potentiometric method.
Conductivity method.
Dissolution rate method.
Liquid-Liquid partition method.
Spectrophotometric method.
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SOLUBILIZATION
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Cosolvency:-
Solubilization by surfactant:-
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.
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THERMAL EFFECT:-
ln S = -Hs/R*T + C
DISSOLUTION
The absorption of solid drugs administered orally can be
understood by following flowchart.
Kd Solution Ka Drug in
Solid drugs systemic
Dissolution of drug in Absorption
in GI fluid circulation
GI fluid
dC/dt = AD(Cs-C) / hv
STABILITY ANALYSIS
Development of a drug substance into a suitable dosage form
requires the preformulation stability studies as:
[1] Solid state stability.
[2] Solution state stability.
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Stress conditions used in
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 & 37C.
Reflux in 1M HCl & 1M NaOH.
Light UV (254 & 366 nm) & Visible at RT.
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.
1) Oxygen concentration.
2) Light.
5) Temperature.
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Prevention of oxidation:-
1) Reducing oxygen content.
6) Addition of an antioxidant.
a.Reducing agent.
b.Chain inhibitors of radical induced decomposition
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ANTIOXIDANT
Addition of surfactant:
Nonionic, cationic & anionic surfactant stabilizes the drug
against base catalysis.
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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
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PHOTODECOMPOSITION PATHWAYS
N-Dealkylation:
Eg. Diphenhydramine, Chloroquine, Methotrexate.
Dehalogenation:
Eg. Chlorpropamide, Furosemide.
Brown.
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Contd
Decarboxylation in anti-inflammatory agents.
Eg. Naproxen, Flurbiprofen, Benzoxaprofen.
Oxidation.
Eg. Chlorpromazine & other phenothiazines give N- & S-
oxides in the presence of sunlight.
Rearrangement.
Eg. Metronidazole Oxidiazine Yellow color.
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Aq. solution of Lincomycin was irradiated with UV light in
homogenous & heterogenous 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.
Use of Anti-oxidant.
Eg. Photodegradation of Sulphacetamide solution may be
inhibited by an antioxidant such as sodium thiosulfate or
sodium metabisulphate.
Coating:
Pigments like TiO2(IN NIFEDIPINE) / ZnO.
Eg. Photostabilization of Sulphasomidine Tab. by film
coating containing U.V. absorber (Oxybenzone) to protect
color & photolytic degradation.
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RACEMIZATION
The interconversion from one isomer to another can lead to
different Pcokinetic properties (ADME) as well as different
Pcological & toxicological effect.
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POLYMERIZATION
It is a continuous reaction between molecules.
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ISOMERIZATION
It is the process involving change of one structure to another
having same empirical formula but different properties in one or
more respects.
Examples:-
Tetracycline & its dvts. can undergo reversible Isomerization
at pH range 2-6.
Isomerization of tetrahydrouridine.
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DECARBOXYLATION
Evolution of CO2 gas from COOH group containing drugs.
Eg. Solid PAS undergoes decarboxlation 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 occular penetration when given orally.(ORAL DRUG
DELIVERY SYSTEM).
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According to W.H.O.
Hydrolysis and Oxidation are the most common pathways for API
degradation in the solid-state and in solution.
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23/09/2009 PAPER-90101 NITU/M.PHARM/2009-10/LMCP
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