1) Solubility refers to the maximum amount of a substance that dissolves in a solvent to make a saturated solution at a given temperature and pressure. Solubility is important for drug bioavailability and is measured at 4°C and 37°C. 2) Solubility studies include determining intrinsic solubility, pH effects, solubility in solvents and with surfactants. Methods to enhance solubility include changing pH, temperature, adding co-solvents or surfactants. 3) The shake flask method is commonly used to determine drug solubility but analytical methods like HPLC provide direct, sensitive analysis of drug concentrations in solutions. Solubility data is important for preformulation studies

1. DEPARTMENT OF PHARMACEUTICS
Presented BY
Nagabhushan Shet
M. Pharm 1st Year ( I semester)
SOLUBILITY STUDIES
BHARATI VIDYAPEETH (DEEMED UNIVERSITY)
POONA COLLEGE OF PHARMACY, PUNE
Poona College Of Pharmacy, Pune

2. What is solubility?
 The solubility of a substance refers to the amount of substance that passes into the
solution to achieve a saturated solution at constant temperature and pressure.
 The bioavailability of an orally administered drug depends primarily on its solubility in GIT
and its permeability across the cell membrane and this forms the basis for BCS.
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3.  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.
 Solubility should ideally be measured at two temperatures:
4 and 37° C.
 4° c to ensure physical stability.
 37°c to support biopharmaceutical evaluation.
 If solubility is <1mg/ml indicates poor absorption and variable solubility, and there is need to
improve solubility through pre-formulation studies.
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4.  During recent years, the main aim of pharmaceutical R and D is to improve the solubility of lower
soluble drugs.
 Clearly a trend towards higher percentages falling into BCS class ll (high permeability, low solubility)
and lV (low permeability, low solubility )is observed.
 Solubilities of a drug represent the bioavailability of the drug.
REASONS FOR DETERMINING SOLUBILITY
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5. TYPES OF SOLUBILITY
 Quantitative Solubility
 Qualitative Solubility
Descriptive term Parts of solvent required for 1 part of
solute
Very soluble Less than 1
Freely soluble From 1 to 10
Soluble From 10 to 30
Sparingly soluble From 30 to 100
Slightly soluble From 100 to 1000
Very slightly soluble From 1000 to 10000
Practically insoluble or insoluble 10000 and over
solubility-based classification of drugs as per the United
State Pharmacopeia.
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6. Solubility studies include
1. Intrinsic solubility
2. Ph solubility profiling
3. Solubility in pharmaceutical solvents
4. Effects of surfactants
 Intrinsic solubility: It is the equilibrium solubility of the free
acid or free base form of an ionizable compound at a pH where
it is fully unionized.
 pH-solubility profiling: change in pH alters the solubility of
acidic/basic compounds. 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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7.  Solubility in pharmaceutical solvents: To enhance the solubility of pharmaceutical products, add co-
solvents
examples: ethanol, methanol, etc...
 Effect of surfactants: Surfactants are wetting agents that lower the surface tension of a liquid, allowing easier
spreading, and lowering the interfacial tension between two liquids. Surfactants are of two types:
 Ionic Surfactants:
 Cationic: e.g., Cetyl Trimethyl Ammonium Bromide,
Hexadecyl Trimethyl Ammonium Bromide, and other Alkyl
trimeth 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
 non-ionic surfactants:
 Water soluble: e.g., long chain fatty acids, fatty alcohols
 Water insoluble:e.g., spans.
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8. PREFORMULATION SOLUBILITY STUDIES
1. Pka determination
2. Effect of temperature
3. Solubilization
4. Partition coefficient
5. Dissolution
1. Pka determination: Determination of the dissociation constant (pka) for a drug capable of
ionization within a pH range of 1 to 10 is important, since solubility and absorption, can be altered
by orders of magnitude with changing pH. Pka values can be determined by the following
methods
a. Potentiometric titration
b. UV spectroscopy
c. Solubility measurement
d. HPLC techniques
e. Capillary zone electrophoresis
f. Foaming activity
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9.  It can be calculated by the Henderson-Hasselbalch equation
2. Effect of temperature: The heat of solution ΔHs, represents
the heat released or absorbed when a mole of solute is
dissolved in a large quantity of solvent.
 Exothermic reaction
 Endothermic reaction
3. Solubilization: It is defined as the spontaneous passage of
poorly water-soluble solute molecules into an aqueous solution
of a surfactant in which a thermodynamically stable solution is
formed
It increases the solubility of a poorly water-soluble substance
with surface-active agents.
Solubilization of any material in any solvent depends on the
proper selection of a solubilizing agent.
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10. 4. Partition coefficient: The partition coefficient, log P, is defined as the ratio of the unionized drug
distributed between the organic and aqueous phases at equilibrium.
The partition coefficient is an important indicator of permeability because the partitioning of a drug into
lipophilic epithelial cells is a necessary step for passive diffusion.
5. Dissolution: Dissolution is the process in which a substance forms a
solution.
• Dissolution testing measures the extent and rate of solution formation from a dosage form, such as tablet,
capsule, etc.
• The dissolution of a drug is important for its bioavailability and therapeutic effectiveness.
• Dissolution and drug release are terms used interchangeably.
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11. Determination of solubility
The following points must be considered:
 The solvent and solute must be pure.
 A saturated solution must be obtained before any solute is removed for analysis.
 The method of separating a sample of saturated solution from an undissolved solute must be
satisfactory.
 The method of analyzing the solution must be reliable.
 Temperature must be adequately controlled.
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12. Method to determine the solubility(shake flask method)
Advantages:
 Most accurate method.
 Accurate for the broadest range of solutes.
Disadvantages:
 Time-consuming.
 Difficult to detect a small amount of undissolved solute.
 Large amount of material is required
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13. Analytical methods for solubility measurements
 HPLC(high performance liquid chromatography)
 UV visible (ultraviolet) spectroscopy
 Fluorescence spectroscopy
 Gas chromatography
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14. Advantages of analytical methods
 Direct analysis of aqueous samples
 High sensitivity
 Specific determination of drug concentration due to chromatographic separation of
drug from impurities or degradation products
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15. Advantages and disadvantages solubility
enhancement techniques
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16. Reference
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 Lachman and Liebermann's “ The Theory and Practice of Industrial Pharmacy” Fourth Edition page
number – 528 to 548.
 Remington, “The Science and Practice of Pharmacy” Volume-I, chapter 2, page number 83 to 98
 Drug Solubility: Importance and Enhancement Techniques Ketan T. Savjani, Anuradha K. Gajjar, and
Jignasa K. Savjani, International journal of pharmaceutics, Volume 19, Article ID 195727,