1) Solubility is the maximum amount of a substance that dissolves in a solvent to form a saturated solution at a given temperature and pressure. 2) Solubility is ideally measured at 4°C and 37°C to ensure physical stability and support biopharmaceutical evaluation. Solubility below 1 mg/ml indicates poor absorption and need for preformulation studies. 3) Preformulation solubility studies focus on the drug solvent system and include determining properties like intrinsic solubility, pH solubility profiles, effects of surfactants, and temperature dependence to understand a drug's solubility and dissolution behavior.

1. SOLUBILITY
and its
DETERMINATION
Prepared By:
Aman Dhamrait Pantlia

2. SOLUBILITY
o 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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3. SOLUBILITY
o 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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4. 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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5. Types of SOLUBILITY
oQuantitative Solubility
oQualitative Solubility
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6. SOLUBILITY
o Thermodynamic Solubility
o Kinetic solubility
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7. USP & IP Solubility
Criteria
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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

8. Biopharmaceutics Classification
system
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9. Solubility Studies include
o Intrinsic Solubility
o pH solubility Profiling
o Solubility in Pharmaceutical solvent
o Effects of Surfactants
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10. 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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11. pH Solubility Profiling
o 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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12. Solubility in Pharmaceutical
solvents
o To enhance the solubility of Pharmaceutical products, add Co-solvents
e.g. ethanol, methanol
o By adding surfactants
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13. Effect of Surfactants
o 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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14. 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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15. Solubility Analysis
o 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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16. Preformulation solubility Studies
o Determination of pKa value (Ionization Constant)
o Temperature dependence
o pH Solubility profile
o Solubility products Ksp
o Solubilization Mechanisms
o Rate of Dissolution.
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17. 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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18. pKa Determination
Can be calculated by Henderson Hasselbalch equation-
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For basic drugs….pH= pKa+ log [unionized drug]
[ionized drug}
For acidic drugs….pH= pKa+ log [ionized drug]
[unionized drug}

19. Effect of temperature
o 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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20. Solublization
o “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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21. Partition Coefficient
o It is the ratio of unionized drug distributed between organic and
aqueous phase at equilibrium.
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P o/w = ( C oil / C water )equilibrium

22. Dissolution
The dissolution rate of a drug substance in which surface
area is constant during dissolution is described by the
Noyes-Whitney equation:
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dc = k (Cs-C)
dt

23. 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 reliable
o Temperature must be adequately controlled .
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24. Method to determine solubility
Shake Flask Method
Advantages
o Most accurate method
o Accurate for broadest range of solutes
Disadvantages
o Time consuming (>30 min /sample)
o Difficult to detect small amount of undissolved solute
o Large amount of material is required
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25. Methods to determine solubility
o Miniaturized shake-flask method
o Semi-automated Potentiometric acid/base titrations
o A computational screening model
o Miniature device
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26. Analytical Methods for Solubility
Measurements
o HPLC ( High Performance Liquid Chromatography)
o UV (ultraviolet Spectroscopy)
o Fluorescence Spectroscopy
o Gas Chromatography
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27. Advantages of Analytical
methods
o Direct analysis of aqueous samples
o High sensitivity
o Specific determination of drug conc. due to
chromatographic separation of drug from impurities
or degradation products
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