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1.physico Chem Properties
1.physico Chem Properties
1.physico Chem Properties
on
Physicochemical factors
Under
Preformulation Study
2 2
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) 37°C 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:-
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:-
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:-
Eg. Gelucire 44/14 is a surface active excipient that can
solubilize poorly soluble drug.
Eg. Anionic & cationic surfactants exhibited dramatically
higher solubilization for gliclazide, while nonionic surfactants
showed significantly lower solubilizing ability.
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Complexation:-
Eg. The complexation of iodine with 10-15% PVP can
improve aq. solubility of active agent.
Formation of Inclusion
Compound:-
Enhanced solubilty of oxicams through inclusion of β-
cyclodextrin and its dvts.
Eg. The enhancement of solubilization increased 300 fold
for Nimodipine at a polymer conc. 10% by use of water
soluble dendrimer based on polyglycerol.
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
of drug
Dissolution Absorption
in GI fluid circulation
in GI
fluid
when Kd<<<<Ka, absorption is dissolution rate limited.
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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
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 & 37ºC.
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.
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. 34 34
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. 35 35
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.
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.
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 P’cokinetic properties (ADME) as well as different
P’cological & 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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