The document discusses various techniques to improve the solubility of poorly soluble drugs, including salt formation, co-solvency, and particle size reduction. It focuses on using salt formation between flurbiprofen and tris(hydroxymethyl)aminomethane to increase solubility. Analytical techniques like DSC, TGA, HPLC, and UV were used to characterize the flurbiprofen-tris salt and showed improved solubility over flurbiprofen alone. The conclusion states that increasing water solubility of insoluble drugs is important for developing effective dosage forms and delivering drugs to the absorption site.

1. GUIDED BY
Mrs. YASMEEN BEGUM
ASST PROFESSOR
(M.pharm)
MALLA REDDY COLLEGE OF PHARMACY
Maisammaguda, Dhulapally (post via
Hakimpet),
Sec-bad-14
PRESENTED BY
C.R.NEETHU
256213885003
M.Pharm (Analysis)

2. CONTENTS
 INTRODUCTION
 SOLUBILITY
 SALT FORMATION
 CO-SOLVENCY
 ANALYTICAL TECHNIQUES
 CONCLUSION

3. INTRODUCTION
• Therapeutic effectiveness of a drug depends
upon the bioavailability and ultimately upon
the solubility of drug molecules.
• Solubility is one of the important parameter to
achieve desired concentration of drug in
systemic circulation for pharmacological
response to be shown.
• Currently only 8% of new drug have both high
solubility and permeability.

4. SOLUBILITY
• Solubility is the maximum quantity of
solute that can dissolve in a certain
quantity of a solvent or solution at a
constant temperature and specified
pressure.

5. Process of solubilization
Step 1:
Holes opens in the solvent.
Step2 :
Molecules of the solid breaks away from the bulk.
Step 3:
The freed solid molecule is integrated into the hole in the solvent.

7. TECHNIQUES TO IMPROVE
SOLUBILITY:
Solubility improvement techniques can be categorized into 3 types:
 Physical Modifications —Particle size reduction like
micronization and nano-suspension, modification of the crystal
habit like polymorphs, amorphous form and co-crystallization,
drug dispersion in carriers like eutectic mixtures, solid dispersions
and solid solutions.
 Chemical Modifications —Change of pH, use of buffer,
derivatization, complexation, and salt formation.
 Miscellaneous Methods —Supercritical fluid process, use of
adjuvant like surfactant, solubilizers, cosolvency,hydrotropy etc.

10. Metal ions
Ammonium
ion
replace
replace
Sodium chloride
Ammonium chloride

11. IDEAL CHARACTERISTICS OF
SALT FORMATION
chemically
stable.
not
hygroscopic.
presents no
processing
problems.
dissolves
quickly from
solid dosage
forms.

12. SALT FORMATION
 Salt formation is one of the simplest chemical
reactions, involving either a proton transfer or a
neutralization reaction between an acid and a base.
 The salt form of a drugs is usually more soluble than
parent drug .
 An alkaloidal base is slightly soluble in water, But if
the pH of medium is reduced by addition of acid, the
solubility of the base increases. The reason for this
increase in solubility: as the pH continues to reduce,
the base is converted to a salt, which is relatively more
soluble in water.
 Examples include Atropine , Bupivacaine, etc.

13. The solubility of slightly soluble acid is increased as the pH is
increased by addition of alkali, the reason being that a salt is
formed.
Examples include Aspirin , Theophylline , Barbiturates .
Compound Solubility (mg/ml)
Naproxen 0.07
Naproxen Na 266
Tolmetin 0.1
Tolmetin Na 163
Bupivacaine 0.05
Bupivacaine HCl 175

14. Use of Salt Form
 Salts have improved solubility and dissolution characteristics in
comparison to the original drug.
 It is generally accepted that a minimum difference of 3 units between
the pKa value of the group and that of its counter ion is required to
form stable salts.
 Alkali metal salts of acidic drugs like penicillin’s and strong acid
salts of basic drugs like atropine are water soluble than the parent
drug
 Salt formation is frequently performed on weak acidic or basic
drugs because it is a relatively simple chemical manipulation, which
may alter the physicochemical formulation, biopharmaceutical,
and therapeutic properties of a drug without modifying the basic
chemical structure.

16. CO-SOLVENCY
• The solubility of a poorly water soluble drug can be
increased by the addition of a water miscible solvent
in which the drug has a good solubility. This whole
procedure is known as co-solvency and the solvent is
called co-solvents.
• Co-solvents are mixtures of water and one or more
water miscible solvents used to create a solution with
enhanced solubility for a poorly water soluble drug.
• It is commonly referred to as solvent blending.

17. Characteristics of Co-Solvents
Non toxic.
Non
irritant.
Able to
solubilize
the drug in
given
solvent.
Able to
cross the
membrane

18. SOME EXAMPLES OF CO-SOLVENTS
GLYCERINE
SORBITOL
PEG
ETHYL CARBAMATE
DIMETHYL ACETAMIDE
GLYCOFUROL

19. MECHANISM OF CO-SOLVENT :
Mechanism responsible for solubility enhancement
through co-solvency is by
 Reducing the interfacial tension (polarity
differences) between the aqueous solution and
hydrophobic solutes.
 Reducing the contact angle between solid and
liquid.
Co-solvents can increase the solubility of a nonpolar
drug up to several orders of magnitude compared to its
aqueous solubility.

20. Solubilization by Co-solvents:
• Weak electrolytes and non polar molecules have
poor aqueous solubility. Their solubility in water
is increased by addition of water miscible solvents
in which drug has good solubility .
• The cosolvents such as propylene glycol,
polyethylene glycol, ethanol, glycerin aid in
solubilizing the drug in aqueous vehicle.
• The solubilizing effect by cosolvency primarily
dependent upon the polarity of drug with respect
to solvent and cosolvent.

22.  Several analytical techniques were used for the
purpose of salt identification and solubility
dissolution rates investigations, these techniques
included NMR, FT-IR, and TLC.
 Analysis for salt formation confirmation, XRD
characterization of the salt material, thermal
analysis included DSC, TGA, and HPLC.
 For qualification and quantification of the new
crystals pH-solubility studies and finally intrinsic
dissolution rate studies.

23. The role of counter-ion in salt formation to improve the
solubility of poorly water soluble drugs in the case of
Flurbiprofen and Tris(hydroxymethyl)amino methane
• This study shows the role of salt formation in
improving the solubility and dissolution rates of
Flurbiprofen, which is one of the poorly water
soluble drugs.
• Tris[hydroxymethyl]aminomethane was used as
a counter-ion and the Flurbiprofen-Tris salt was
crystallized from acetonitrile as solvent.

24.  Flurbiprofen: is a non-steroidal anti-inflammatory drug
(NSAID) that readily forms carboxylic acid salts. It is
administered for its anti-inflammatory, antipyretic, analgesic
effects, and to inhibit intraoperative mitosis.
 Tris[hydroxymethyl]aminomethane: was used as a
counter-ion .
 Acetonitrile: is a polar solvent that used to crystallize the
Flurbiprofen-Tris salt .
MSc presentation project 24
EXAMPLE :

25. The Flurbiprofen and Tris [hydroxy methyl]amino methane were
combined to prepare an soluble salt, which was then precipitated
and yield the final product.
MSc presentation project
- +
3
Acetonitrile
Flurbiprofen
Tris[hydroxymethy
l]aminomethane
The
equation
reaction
reactants product
Flurbiprofen-
Tris salt
Solvent

26.  Differential Scanning Calorimetric (DSC)
 Thermo Gravimetric Analysis (TGA)
 High Pressure Liquid Chromatography (HPLC)
 Ultra Violet spectroscopy (UV)
MSc presentation project 26

27. Analytical methods:
Differential Scanning Calorimetric (DSC)
Several experiments were attempted to resolve and identify all obtained
peaks by once changing the N2 gas flow rate for a better expansion for
the DSC curve.
The DSC curve in Flurbiprofen shows a
sharp endothermic peak representing
the melting point of pure Flurbiprofen
at (113.950C). The sharpness of the
peak and absence of any others within
the temperature range of the
experiment indicates that this material
is reasonably pure.
The DSC curve in Flurbiprofen-Tris salt
which formed by using acetonitrile as
solvent gave a two exothermic peaks at
temperatures of 129.030C - 137.640C
indicating a polymorphic crystalline
internal structure for the Flurbiprofen-
Tris salt.
113.950C
137.640C
MSc presentation project 27
129.030C
Pure
Flurbiprofen
Flurbiprofen-Tris
salt

28. Analytical methods:
Thermo Gravimetric Analysis (TGA)
The weight is steady until
160oC
For Flurbiprofen and its salt, the weights of the samples were steady
until 160oC, and then a dramatic change happened from 160oC until
260oC.
• The weight loss of the Flurbiprofen was 1.637mg (54.5%).
• The weight loss of the Flurbiprofen-Tris salt was 1.966mg
MSc presentation project 28
(50.3%).
The weight is steady until
160oC
The weight loss of the
Flurbiprofen is 1.637mg
(54.5%)
The weight loss of the
Flurbiprofen-Tris salt is 1.966mg
(50.3%)

29. Analytical methods:
High Pressure Liquid Chromatography (HPLC)
Flurbiprofen-Tris saturated
salt
Conc. Using HPLC (mol/ml)
Saturated salt 1 5.43477E-04
Saturated salt 2 4.92823E-04
Saturated salt 3 4.95105E-04
The mean of saturated salt 5.10500E-04
MSc presentation project 29
Conc. (ppm) Conc. Of
Flurbiprofen
(mol/ml)
Conc. Of
Flurbiprofen-Tris
salt (mol/ml)
10 3.97100E-05 2.84643E-05
25 1.01118E-04 6.97923E-05
50 2.10014E-04 1.32468E-04
75 3.05400E-04 2.05545E-04
100 4.08564E-04 2.75064E-04
The figure shows a linear relationship between
the concentration and the peak area for both
the Flurbiprofen and the Flurbiprofen-Tris salt.
Both compounds were soluble, but the
Flurbiprofen-Tris salt had lower solubility based
on its sigma value, when compared to the sigma
value of Flurbiprofen
The HPLC calibration curve equations for
Flurbiprofen-Tris allowed calculation of the
amount of salt that has been dissolved in
water at a ratio of 1:1 (water:salt).

30. Analytical methods:
Ultra Violet spectroscopy (UV)
Flurbiprofen-Tris saturated
salt
Conc. Using UV (mol/ml)
Saturated salt 1 527.2689301
Saturated salt 2 479.0071659
Saturated salt 3 481.1811309
The mean of saturated salt 495.81908
The UV calibration curve equations
for Flurbiprofen-Tris allowed
calculation of the amount of salt that
has been dissolved in water at a ratio
of 1:1 (water:salt).
MSc presentation project 30
Conc. (ppm) Conc. Of
Flurbiprofen
(mol/ml)
Conc. Of
Flurbiprofen-Tris
salt (mol/ml)
0.1 3.47976E-07 2.73695E-07
0.2 8.59704E-07 6.29499E-07
0.3 1.26909E-06 8.48455E-07
0.4 1.47378E-06 1.04004E-06
0.5 1.92410E-06 1.25900E-06
0.6 2.74287E-06 1.61480E-06
0.7 3.07037E-06 1.97061E-06
0.8 3.35694E-06 2.21693E-06
0.9 3.64351E-06 2.49063E-06
1.0 3.93008E-06 2.73695E-06
The figure shows a linear relationship for the absorbances of Flurbiprofen and the Flurbiprofen-
Tris salt. The overall absorbance of Flurbiprofen-Tris salt was lower than that for Flurbiprofen.

31. CONCLUSION
 The aqueous solubility of drug is often a limiting factor in developing most
desirable dosage form.Hence, Increasing the water solubility of insoluble or
slightly soluble compounds is of major concern for pharmaceutical
researchers.
 A highly solubilized formulation is desired to minimize
dissolution limited absorption.
 Newly developed techniques could bridge the gap between dissolution and
absorption for many such drugs.Research in this area still continues to be
promising and challenging for optimization of the drug delivery