PHA 6113

PHYSICAL PHARMACY
LABORATORY
ACTIVITY 2
SOLUBILITY

SOLUTION
• A homogenous dispersion of two or more substances
in each other

• Saturated Solution – a solution containing the

maximum concentration of a solute dissolved in the
solents. (clear solution) (inequilibrium)
• Equilibrium – equal amounts of solutes and solvent
• Unaturated solution – more solute dissolves; lesser
amount of solute (clear solution)
• Supersaturated solution – added crystals grow;
greater amount of solute (precipitate or formation of
crystals or sediments)
Units of concentration – molality, mole fraction, mole
ration, percentage concentration, w/w, w/v, v/v
USP 43 (2020)
• Two components
• SOLUTE (dissolved substance)
DISSOLUTION
• SOLVENT (dissolving/dispersion medium)
• The non-equilibrium process of approaching the
Not all solution is made of solid and liquid, they may
solubility limit at thermodynamic equilibrium
also made up of liquid and liquid → emulsion
• Dissolution rate – how quickly the solubility limit is
Insoluble solid and liquid → suspension
reached; affect the time required to reach equilibrium
Sometimes, gases and liquid
and may affect the apparent solubility but not the final
solution; However, the dissolution is not the final
SOLUBILITY
equilibrium or solubility
• The amount of solid that passes into the solution
• Solubility – is the amount of substance dissolved in
when equilibrium is established between the solution
the dissolution
and excess or undissolved substances
USP 43 (2020)
• The capacity of the solvent to dissolve a solute
Amount of solute that can be dissolve in solvent
USP OFFICIAL EXPERIMENTAL METHODS
• Once the amount of solute is in equilibrium, a
• Methods for Determination of Equilibrium Solubility
saturated solution will be formed.
• Saturation Shake-Flask method -

• Methods for Determination of Apparent Solubility

• Intrinsic Determination
• Potentiometric Titration
• Turbidimetry
• Physical Assessment of Solubility
USP 43 (2020)
 EQUILIBRIUM SOLUBILITY 2. EQUILIBRATION OF SOLUTION
• The concentration limit, at thermodynamic • Actively mixed or agitated for 24 hours (you will see
equilibrium, to which a solute may be uniformly excess solid – will settle at the bottom. This excess solid
dissolved into a solvent when excess solid is present will not dissolve, but it will become a sediment or a
• Equilibrium – defined as efficiently converge when layer at the bottom)
there will be no longer changes in certain time frmae • Allow sedimentation for excess solid. Decant or siphon
off the liquid to separate the sediment to the solution
SATURATION SHAKE-FLASK METHOD leaving the solid undisturbed in the bottom of the flask.
• You need a flask and you need to shake it Or if there are suspended small particles then filter the
• Based on phase solubility technique solution.
• Considered as the most reliable and widely used • The objective of this process is to get the saturated
method for solubility solution only.
• Sedimentation or decantation is the safest separation
of excess solid from the saturated solution

3. ANALYSIS OF SOLUTION
• Method should be linear and specific
• Liquid: UV-Vis spectroscopy (result will be
absorbance) or by HPLC
METHODS: • Use HPLC – the result will be the area under the curve
1. First, get the flask and add the compound that will be the peaks
2. Then put the solvent and shake up to 10-15 minutes • This is use in determining the solubility of the solid
or depending on the protocol sample
3. Submit to incubation for 24 hours, if there are excess • Excess solid: Verify identity by Powder X-ray
solid or sediments, decant the liquid or scoop out the diffraction, Raman or NIR Spectroscopy or evaluate
sediment. If fine particles are suspended in the melting point
solution, you can subject it to filtration to discard the
residues 4. REPORTING OF SOLUBILITY RESULTS
4. Do the elution then to HPLC analysis (High-precision • Solubility value should be reported at the pH value
Liquid Chromatography) You will get area under the and temperature observed at the end of equilibration
curve which will be used to compute for the different step
solubility of the different sample. In HPLC, you will
need a small amount of concentration. No need to APPARENT SOLUBILITY
amount the solid or volume. The accucracy will not be • Empirically determined solubility of a solute in a
affected by the amount of solvent or solute. That is solvent system where insufficient time is allowed
why we need to dilute, just like a concentration that is for the system to approach equilibrium or where
readily read by the HPLC. equilibrium cannot be verified
• Equilibrium solubility – we observe equilibrium
SATURATION SHAKE-FLASK METHOD meaning there is a balance in the solute and the
1. SAMPLE PREPARATION solvent. That is the solute contain in the solution is the
• Add excess solid to solubility medium in a flask or vial maximum amount of solute that the solvent can
(no need take the amount of the solvent but it is also dissolve
recommended) • While apparent solubility - Either higher or lower
• Increase the surface area by grinding or triturating it than the equilibrium solubility due to transient
with mortar and pestle – It will increase the interaction supersaturation or incomplete dissolution due to
of solute and the solvent and will aid in the solubility of insufficient time to reach equilibrium
the solute. • Apparent solubility can be affected by
• Recommended: 1-2 g/mL in excess of the estimated physicochemical, surface area, particle size, and the
solubility crystal form of the solids
• Performed in triplicates (three trials). At the end, you
take the average to compute for the solubility ratio
APPARENT SOLUBILITY OFFICIAL METHODS • Solubility is estimated by back-extrapolation to the
• INTRINSIC DETERMINATION start of precipitation
• POTENTIOMETRIC TITRATION • The apparatus that will be used will be UV-VIS
• TURBIDIMETRY Spectrophotometer
• PHYSICAL ASSESSMENT OF SOLUBILITY
C. PHYSICAL ASSESSMENT OF SOLUBILITY
METHODS FOR DETERMINING • More organoleptic in nature, so you use your senses
APPARENT SOLUBILITY to perform this. Compared with the other method, this
A. Intrinsic Determination aka Intrinsic solubility is on the subjective side and not going to use any
• A measurement of intrinsic (inside) dissolution apparatus or machine.
• Dissolution experiment must be continued to the • Only applicable for solid materials
point that the rate of dissolution is insignificant • For compounds with extremely high solubility
• The solubility of the uncharged or neutral solubility. • Principle: Loss of solid material to the solution phase
We focus on the uncharged or neutral ion with no sign. • Assessed by stability of the weight loss and change in
• Same acceptance criteria with Saturation Shake-Flask physical properties of the resulting solution
Method – the result is in consideration with the pH and • Biologics and other molecules that lack chromophores
temperature for the solubility to be examined • We consider refractive index, density, post molality,
and some other concentration of solvents to be used
B. POTENTIOMETRIC TITRATION and solid substances to be dissolve.
• In tritration, there is a solution which has a positive or
negatively charged, pH will also be considered. There
will be analyte and a standard because it is a titration. PROCEDURE FOR SIMULATION OF SATURATED SHAKE-
And if it will be caused by precipitation, when it involves FLASK METHOD
gravimetric analysis.
• Based on characteristic shift in the middle of
titration curve caused by precipitation
• Accurate volumes of standard acid or based are
added to a solution containing ionizable substance
and a salt (Dissolve a sample in a solvent then you will
use your titrant and indicator. You will keep titration
until the amount of titrant is reached to a point that
there will be a change or reach and end point. End
point will be know if there will be change in the color Erlenmeyer flask (sample + 20mL dist water)
of solution. If soluble (add sample until insoluble)
• A glass electrode is used to monitor the pH value If insoluble (shake for 15 minutes)
continuously If soluble (add sample until insoluble)
• Potentiometric titration curve is obtained by plotting If insoluble (FILTER)
the pH value against the consumed volume of acid or
base 1. Add big amount of solute to your solvent
(solvent is 20mL distilled water) and shake.
TURBIDIMETRY 2. Add excess of the solid until such time that
• Dissolution of a compound in an organic solvent there will be the formation of the precipitate; a
• Solution is added to a buffer solution in intervals turbidity or sedimentation. There should be
adequate to characterize changes in turbidity (a excess solid at the end will solidify or settle at
solution with a precipitate) the bottom.
• Further aliquots of a solution are added after the 3. A. If soluble, add and add your solute until it
first detection of turbidity by light scattering becomes soluble.
• At this point, turbidimeter that will measure turbidity B. If insoluble, continue shaking for 15 minutes
which will be equivalent to concentration or agitate or use sonicator
• Remember that adsorbance and concentration has 4. If it dissolves, continue adding the solid until the
direct proportionality. The higher adosrbance in UV-VIS, solids become unsoluble.
the higher the concentration of the solution. Rationale of adding too much of the solute (solid) – you
want to determine the solubility of the solute and with
the excess solid. Determine the solubility of the solution SOLUBILITY RATIO
with the excess solid. The excess solid will become • volume of water that dissolves one gram of the
insoluble when it reaches its maximum solubility - It will sample
form a supersaturated solution. When there is
insolubility, filter it.

USP Relative Terms of Solubility

Description Parts of Solvent required for 1 part
of Solute
Very Soluble <1
In filter, you discard the precipitate or residue. You will Freely Soluble 1-10
only collect the filtrate. And from the filtrate you are Soluble 10-30
going to pipet 5mL of this filtrate. You put it in the Sparingly Soluble 30-100
evaporating dish (D1 – 5mL of the filtrate) and another Slightly Soluble 100-1,000
5 mL from the filtrate in another evaporating dish (D2 – Very Slightly Soluble 1,000-10,000
5mL of the filtrate) Practically Insoluble >10,000

Sample Problem (Solubility Ratio)

• A pinch amount of solid sample was dissolved in a
bucket of water. The solution was sonicated for 30
minutes. 30 mL of the filtered solution was placed in an
evaporating dish weighing 126.1118 g. After drying in
the oven at 105⁰, the evaporating dish now weighs
126.2889 g. Determine the solubility ratio.

Data: Weight of empty evaporating dish: 126.1118 g

Weight of empty evaporating dish + sample: 126.2889 g
Volume of solution: 30 mL
Heat the two evaporating dish on the Memmert oven at
105degrees centigrade or depending on the
monograph. You can also put them on hot plate until
dried. Hot plate is used to hasten the evaporation.
Memmert oven is sometimes used and when it has
completely evaporated, you will cool it first by putting it
in a dessicator. And when it is cool already, you will
weigh in the analytical balance. Weigh D1 which will be
called D1F and D2 will then be weighed called D2F

DATA Solubility Ratio: 1:169.40 - SLIGHTLY SOLUBLE

• D1 – initial weight of first evaporating dish
• D1f – final weight of first evaporating dish
• D2 – initial weight of second evaporating dish
• D2f – initial weight of second evaporating dish

• Weight of sample 1 = D1f – D1

• Weight of sample 2 = D2f – D2
• Get the average sample weight
Factors Affecting Solubility and Solubility Measurements IMPORTANCE
Effect of pH • For prediction of the drug delivery characteristics of a
• Various pH affects solubility like acid dissolves in dosage form and characterization of a drug as either
base and base dissolves in acid high or low solubility in the BCS (Biopharmaceutics
• Strong acids (HCl, Nitric acid, Sulfuric Acid, Classification system)
halogenated acid – hydroiodic, perchloric, • In BCS, we classify drugs based on their solubility and
hydrobromic) completely dissociate into their ions permeability. Solubility based on the solute dissolving in
in water the solvent. Permeability is the extent of which drug
• Weak acids only partially dissociate products is absorbed readily in our body system.
• For understanding both quality control and drug
Effect of salts and counter-ions delivery issues of pharmaceutical formulations
• Common ion effect • For identification and descriptive purposes
• Solubility will help us categorize different drug
Effect of co-solvents products regarding their drug delivery characteristics.
• Involvement of multiple solvents
• Added to a mixture of two or more separate
substances that are typically immiscible to mix
them
• Use of cosolvent will increase solubility (alcohol
due to hydroxyl group – will dissolve in
hydrophobic molecules which is not so soluble in
water)

Effect of surfactants
• HLB values

Effect of complexing agents

• A compound in which independently existing
molecules or ions of a nonmetal form coordinate
bonds with a metal atom or ion
• Increase solubility but decrease absorption
• Dairy products – form an interaction with
tetracycline or chlorphenones forming now
acylation. It will produce chelates or the complex
agents and these are normally the interaction or
food-drug interaction that we will encounter.
These are the coordinated bonds with a metal ion
or ion

Effect of surface area (Dissolution rate)

• Greater surface area, better dissolution and
solubility

Effect of surface energy (Nanoparticles)

• Charged small compounds (like surface area)

• Temperature
• Pressure
• Polarity and Hydrogen Binding
• Solute-Solvent Interactions
• Particle Size
• Boiling Point
• Melting Point