solubility and its determination
TRANSCRIPT
SOLUBILITY and its
DETERMINATION
Prepared By:Aman Dhamrait Pantlia
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SOLUBILITYo The solubility of a substance refers to the
amount of substance that passes into solution to achieve a saturated solution at constant temperature and pressure.
o Solubility= Maximum volume/mass of thesolute volume of a solvent
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SOLUBILITYo One way of measuring solubility is to determine
the maximum mass of solute that can be dissolved in 100 ml of solvent at a particular temperature.
o Solubility should ideally be measured at two temperatures: 4°c and 37°c.- 4°c to ensure physical stability.- 37°c to support biopharmaceutical evaluation.
o If solubility is <1mg/ml indicates poor absorption, erractic solubility and need to improve solubility by preformulation studies.
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Reasons for Determining Solubility
o During recent years, considerable change in the solubility of pharmaceutical R&D compounds and drugs towards lower solubility.
o Clearly a trend towards higher percentages falling into BCS class II (high permeability, low solubility) and IV (low permeability, low solubility) is observed
o Solubilites of a drug represent the Bioavailability of the drug.
o For efficient drug delivery
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Types of SOLUBILITYoQuantitative Solubility
oQualitative Solubility
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SOLUBILITY
oThermodynamic
Solubility
oKinetic solubility
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USP & IP Solubility Criteria
Description Parts of solvent required for one part of solute
Very soluble < 1 Freely soluble 1 - 10
Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000
Very slightly soluble 1000 - 10,000 Insoluble > 10,000
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Biopharmaceutics Classification system
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Solubility Studies include
o Intrinsic Solubilityo pH solubility Profilingo Solubility in Pharmaceutical solvento Effects of Surfactants
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Intrinsic Solubility Intrinsic solubility is the equilibrium solubility of
the free acid or free base form of an ionisable compound at a pH where it is fully un-ionised. Equilibrium solubility is the concentration of compound in a saturated solution when excess solid is present, and solution and solid are at equilibrium.
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pH Solubility Profilingo Changes in pH- Altered the solubility of acidic /basic
compounds.o The solubility of an acidic or basic drug depends on the pKa of
the ionizing functional group and the intrinsic solubilites for both the ionized and un-ionized forms.
o pH solubility profile of a drug can be established by running the equilibrium solubility experiment within pH range of 3-4.
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Solubility in Pharmaceutical solventso To enhance the solubility of Pharmaceutical products, add
Co-solvents e.g. ethanol, methanolo By adding surfactants
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Effect of Surfactantso Surfactants are wetting agents that lower the surface
tension of a liquid, allowing easier spreading, and lower the interfacial tension between two liquids.
o Surfactants are of two types: Ionic Surfactnats:− Cationic: e.g. Cetyl Trimethyl Ammonium
Bromide ,Hexadecyl Trimethyl Ammonium Bromide, and other Alkyltrimethyl Ammonium Salts, Cetylpyridinium Chloride
− Anionic: e.g. Sodium Dodecyl Sulphate , Ammonium Lauryl Sulphate and other alkyl sulfate salts, Sodium Lauryl Sulphate, also known as Sodium Lauryl Ether Sulphate (SLES).
− Zwitterionic: e.g. Phospholipids, phosphatidylethanolamine, phosphatidylcholine
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Effect of Surfactants
o Non-Ionic Surfactants:− water soluble: e.g. Long chain fatty acids,
fatty alcohols− water insoluble: e.g. spans
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Solubility Analysiso Preformulation solubility studies focus on
drug solvent system that could occur during the delivery of drug candidate.
o For e.g. A drug for oral administration should be examined for solubility in media having isotonic chloride ion concentration and acidic pH.
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Preformulation solubility Studies
o Determination of pKa value (Ionization Constant)o Temperature dependenceo pH Solubility profileo Solubility products Kspo Solubilization Mechanismso Rate of Dissolution.
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PKA Determination Determination of the dissociation constant (pKa) for a
drug capable of ionization with in a pH range of 1 to 10 is important, since solubility and absorption, can be altered by orders of magnitude with changing pH.
o Determination of pKa value by Ultraviolet spectroscopy
o By Potentiometric Titrations
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pKa DeterminationCan be calculated by Henderson Hasselbalch equation-
For basic drugs….pH= pKa+ log [unionized drug]
[ionized drug}
For acidic drugs….pH= pKa+ log [ionized drug]
[unionized drug}
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Effect of temperatureo The heat of solution Hs, represents the heat
released or absorbed when a mole of solute is dissolved in large quantity of solvent.
− Endothermic reaction− Exothermic reaction
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Solublizationo “Solubilization is defined as the spontaneous passage of
poorly water soluble solute molecules into an aqueous solution of a surfactants in which a thermodynamically stable solution is formed ”.
o It is the process by which apparent solubility of an otherwise sparingly soluble substance is increased by the presence of surfactant micelles .
o Solubilization of any material in any solvent depends on proper selection of solubilising agents.
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Partition Coefficiento It is the ratio of unionized drug distributed between
organic and aqueous phase at equilibrium.
P o/w = ( C oil / C water )equilibrium
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Dissolution The dissolution rate of a drug substance in which
surface area is constant during dissolution is described by the Noyes-Whitney equation:
dc = k (Cs-C) dt
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Determination of Solubilities
The following points should be considered:o The solvent & solute must be pure.o A saturated solution must be obtained before any solution
is removed for analysis.o The method of separating a sample of saturated solution
from undissolved solute must be satisfactory.o The method of analyzing solution must be reliableo Temperature must be adequately controlled .
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Method to determine solubility
Shake Flask MethodAdvantageso Most accurate methodo Accurate for broadest range of solutes
Disadvantageso Time consuming (>30 min /sample)o Difficult to detect small amount of undissolved soluteo Large amount of material is required
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Methods to determine solubilityo Miniaturized shake-flask methodo Semi-automated Potentiometric acid/base titrationso A computational screening modelo Miniature device
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Analytical Methods for Solubility Measurements
o HPLC ( High Performance Liquid Chromatography)
o UV (ultraviolet Spectroscopy)o Fluorescence Spectroscopyo Gas Chromatography
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Advantages of Analytical methods
o Direct analysis of aqueous sampleso High sensitivityo Specific determination of drug conc. due to
chromatographic separation of drug from impurities or degradation products
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