This presentation is regarding different solubilization techniques in pharmaceutical sector to over come solubility problems.

1. SOLUBILIZATION TECHNIQUES
By Prashant Patel

2. Content:
• 1. COSOLVENCY
• 2.COMPLEXATION
• 3. SALT FORMATION
• 4.MICRONIZATION
• 5.SELECTIVE ADSORPTION

3. Why solubilization techniques are needed?
• Solubility is essential to a drug’s success. Most drugs
are organic and will not go into an aqueous solution
easily.
• There are several different ways to enhance
solubility, and the method of choice depends on the
nature of the solute, the required degree of
solubilization, and other formulation restrictions
such as drug stability and compatibility with
therapeutic use.

4. 1.Co-solvency:
• definition :
The solubility of a poorly water soluble drug can be increased frequently
by the addition of a water miscible solvent in which the drug has good solubility
and such technique is known as co-solvency.
• Cosolvents are mixtures of water and one or more water miscible
solvents used to create a solution with enhanced solubility for
poorly soluble compounds .
• Co-Solvents can increase the solubility of poorly soluble compounds several
thousand times compared to the aqueous solubility of the drug alone.
• Very high drug concentrations of poorly soluble compounds can be dissolved
compared to other solubilization approaches.

5. Mechanism of co-solvency:
Favours the dissolution of a non-polar solute
Decreases intermolecular H-Bonding interactions of
water
Decreases the ability of water to “squeeze out” a non-
polar organic solute
Lower overall polarity than a purely aqueous system

6. Advantages:
• Simple and rapid to formulate and produce.
• Co-solvents may be combined with other
solubilization techniques and pH adjustment to
further increase solubility of poorly soluble
compounds.

7. Disadvantages:
• As with all excipients, the toxicity and tolerability related
with the level of solvent administered has to be considered.
• Uncontrolled precipitation occurs upon dilution with
aqueous media. The precipitates may be amorphous or
crystalline and can vary in size.
• Many of the insoluble compounds shares works which are
unsuited to co-solvents alone, particularly for intravenous
administration.
• This is because the drugs are extremely insoluble in water
and do not readily redissolve after precipitation from the co-
solvent mixture.
• In these situations, there is a potential risk for embolism
and local adverse effects at the injection site.

8.  Commonly used Cosolvent
• Glycerol
• Propylene Glycol
• PEG 400
• Dimethyl Sulfoxide
• Dimethyl Acetamide
• Ethanol
• n-Octanol
• Glycerol
Cosolvents used in Drugs
• Diazepam (Valium) -10 % ethanol and 40 % PG
• Benzocaine(Aerbesol)- 70 % Ethanol

9. Co-solvent products:
• Nimodipine Intravenous Injection
(Nimotop®, Bayer)
• Digoxin Elixir Pediatric
(Lanoxin®,GSK)

10. 2.Complexation:
• There are numerous examples in the literature of
drugs whose solubility and hence bioavailability
have been increased the use of cyclodextrins: they
include piroxicam,itraconazole, indamethacin,
pilocarpine, naproxen,hydrocortisone, diazepam
and digitoxin.
• The first product on the UK market containing a
cyclodextrin is the poorly soluble antifungal
itraconazole,which has been formulated as a liquid
dosage form with the more soluble derivative of ^-
cyclodextrin.

11. Two types of Complexation :
Self association and Stacking Complexation
• Stacking complexes are formed by the overlap of
planar regions of aromatic molecules.
Inclusion Complexation
• inclusion complexes are formed by the insertion of
the nonpolar region of one molecule into the cavity
of another molecule (or group of molecules).

12. The mathematical description for the equilibrium
constant of a 1:1 complex, K1:1 is defined by
The equilibrium constant is also commonly referred to
as the stability constant or the complexation constant.

13. Self association and Stacking Complexation
Organic drug+water Nonpolar moieties are Squeezed out by
strong water-water interaction force
Forms aggregates
Minimize the contact with water by aggregation of their
Hydrocarbon moieties
Large planar nonpolar regions
Opposed by entropy
Random arrangement
Complexes stacked can be homogenous or
mixed
SELF
ASSOCIATION
COMPLEXATION

14. Examples of substances that interact
in an aqueous media by stacking are,
• Naphthalene
• Pyrene
• Benzoic acid
• Methylene blue
• Caffeine etc.

15. Inclusion Complex
• Produced by the Inclusion of a nonpolar molecule or the
nonpolar region of a molecule (Guest) into the nonpolar
cavity of another molecule or group of molecules ( Host).
• When the guest molecule enters the host molecule the
contact between water and the nonpolar regions of both is
reduced.
• The most commonly used host molecules are the
CYCLODEXTRINS.

16. Cyclodextrin
• These cyclic oligomers of glucose are relatively soluble in water
and have cavities large enough to accept common nonpolar
portion of the drugs.
• The characteristic nature and structure of Cyclodextrin makes its
place in pharmaceutical excipients.
• Cyclodextrins (CDs) can enhance apparent water solubility by
forming dynamic, non-covalent, water-soluble inclusion
complexes

17. The Natural Cyclodextrins
• α-Cyclodextrin
α-CD is of limited value due to low complexation
efficiency with most drugs.
• β-Cyclodextrin
β-CD does not usually posses rather good complexation
efficiency with drugs. However β-CD and its complexes have
very limited aqueous solubility.
• γ-Cyclodextrin
γ-CD has frequently lower complexation efficiency than β-CD.

18. Complex formation:
• Complexation of ketoprofen with Hydroxypropyl β-CD.
 The inclusion complex 0f KPF- 2 HPβ-CD could be formed spontaneously and
lower temp is benefit to the formation. Hence, the solubility of KPF in aqueous
solution increase.
Example:

19. Advantages of - Cyclodextrine
• It converts liquid drugs to microcrystalline
powders.
• Volatile component can be stabilized against losses
through evaporation.
• Molecules can be protect against oxidation.
• It can be used for taste and smell masking.
• Incompatible drug can be mixed together if one of
them is protected by formation of Cyclodextrine
complex.
• Solubility in water as well as the rate of dissolution
of poorly soluble drug can be increased.

20. Limitation of Complexation
• These are very expensive materials.
• In some cases when the complexing agent is too concentrated, the
complex can precipitate out of solution as more complexing agent is
added.
• The sensitive nature of corneal epithelium precludes the use of
certain cyclodextrins due to their toxicity.
▫ Ex-Jansen and coworkers found that dimethyl-b-cyclodextrin is toxic to
the cornea and thus should not be used for corneal ophthalmic
formulations
• Natural cyclodextrins are not useful for parenteral drug delivery as
they posess renal and cytotoxicity.some of the chemically modified
Cyclodextrins are used.
▫ Ex: Hydroxypropyl and sulfobutyl ether derivatives.
• β-Cyclodextrin is not useful for parenteral drug delivery.
• limiting factor for the use of cyclodextrins is the ability of a drug to
form a complex with the cyclodextrin internal cavity. The entrance to
the cavity of cyclodextrins may have hydroxyl groups or bulky alkyl
groups that may provide steric restrictions to the encapsulation of
drugs

21. 3.Salt Formation: Why?
• Salt formation is frequently performed on weak
acidic or basic drugs
• The ideal characteristics of a salt are that it is
chemically stable, not hygroscopic, presents no
processing problems, dissolves quickly from
solid dosage forms (unless it is formed with the
intent to delay dissolution) and exhibits good
bioavailability.)

22. Selection Of Salt:
• Weakly acidic drugs , a strong base salt is prepared such
as the sodium and potassium salts of barbiturates and
sulphonamides.
• Weakly basic drugs , a strong acid salt is prepared like
hydrochloride or sulphate salts of alkaloidal drugs
(Atropine)
• Size of the counter ion influence the solubility of salt
forms of the drug.
• Smaller the size of the counter ion , greater the
solubility of salt
• Novobiocin from its sodium salt , calcium salt and free
acid form was found solubility in the ratio – 50:25:1

23. INORGANIC SALTS
• Salts were found to have the systematic effect on the
behaviour of aqueous solutions & were divided into
kosmotropes (polar water-structure markers) or
chaotropes (water-structure breakers).
• kosmotrope:- A doubly charged ion (e.g So4-2) or an
ion with a high charge density. (e.g. F-) was proposed
to interact with the adjacent water molecules more
strongly than would bulk water.
• chaotrope :- a large ion with a single charge (e.g.
ClO4- or SCN-) was proposed to interact with adjacent
water molecules less strongly than would bulk water

24. Example of inorganic salt:
• Caffeine solubility of Different salts have different
effects on the solubility: Added NaClO4 or NaSCN
increases the caffeine solubility, whereas added
Na2SO4 or NaCl decreased it and added NaBr did not
show any significant effect.

25. The solubility were also treated using the empirical
Setschenow equation:-
The k values are positive for salts that decrease solubility &
negative for salt that increase solubility.

26. Examples of salts:
• Many of the antibiotics administered i.v. are sodium
salts.
• Organic acid salt forms of basic drugs, such as
amines, frequently have higher aqueous solubilities
than their corresponding inorganic salts.
• Solubilization does not always improve the taste. Eg:
potassium salts frequently have an unpleasant taste
and leave a metallic after taste.
• N-Cyclohexylsulfate salts of several drugs have
improved taste and enhanced solubility properties.

27. Advantages of Salt
• It can be effectively applied for the solubilization of
weak acids and bases .
• Different salts(i.e. caffeine) of the same drug can
also be used to generate crystals with different
lattice energies and hence different solubilities.
• dissolves quickly from solid dosage forms (unless it
is formed with the intent to delay dissolution) and
exhibits good bioavailability.
• N-Cyclohexylsulfate salts of several drugs have
improved taste and enhanced solubility properties.

28. Disadvantages of Salt
• Solubilization does not always improve the taste. Eg:
potassium salts frequently have an unpleasant taste
and leave a metallic after taste.
• Selection of an appropriate salt is difficult for desired
solubility .
• It is not feasible to form salts of neutral compounds.
• Difficult to form salts of very weak bases/acids.
• The salt may be hygroscopic , exhibit polymorphism
or has poor processing characteristic.
• Conversion of salt to free acid/base form of the drug
on surface of solid dosage form that prevents or
retards drug release .

29. 4.Micronisation:
• It is a high energy particle size reduction technique that
can convert coarse particles into particles of less than 5 μ
in diameter.
• Generally, desired in pharmaceutics is smaller than 1mm
• By micronization we get uniform and narrow particle size
distribution which is essential for developing uniform dosage
form
• griseofulvin, chloramfenicol, tetracycline salts shows
50% more absorption rate after micronizer.

30. • As micronization occurs surface area increases with
decreasing particle size and solubility increases and
observed solubility increased with decreasing particle size in
accordance this equation :-
• further decreases the particle radius (smaller than micron
level)then it may decreases solubility because any changes on
particle it may affect the static charge present on the particle and
which may decreases the solubility

31. Techniques for Micronization:
• Jet milling
fluid energy mill or micronizer
• Solid solution & eutectic mixtures
• Microprecipitation & microcrystallization
• Controlled crystallization
• Supercritical fluid technology
Supercritical fluid nucleation (SFN)
Gas antisolvent recrystallization
precipitation with compressed fluid antisolvent
• Spray freezing in to liquid

32. RECENT WORK ON MICRONIZATION
• Drug powder properties decisive for pulmonary use.
• A small particle size, a good deagglomeration behaviour
required.
• Several anti-inflammatory drugs Beclomethasone
dipropionate , Betamethasone-valerate , Triamcinolone
acetonide, Prednisolone micronized by controlled
crystallization without any milling processes

33. • Micronized purified flavonoid fraction for chronic
venous insufficiency , venous ulcer and
haerrorrhoids.
• Improvement of dissolution rate of ARTEMISININ
by supercritical fluid tech. and solid dispersion.
• Enhancement of dissolution rate of poorly water
soluble particle by spray freezing into liq. With
atmospheric freeze – drying

34. Advantages:
• Micronization will results in higher dissolution
rates .
• As there is reduction in the particle size it
provides uniform distribution of the drugs in
dosage form .
• Micronization helps in decrease the dose of
certain drugs because of increased absorption
efficiency ,for eg.griseofulvin dose was reduced
to half following micronization .

35. Disadvantages :
The amorphous region are thermodynamically unstable and
therefore susceptible to recrystallization on storage
particularly in hot and humid condition .

36. 5.SELECTIVE ADSORPTION :
• Highly active adsorbent inorganic clay like bentonite
enhance dissolution rate of poorly water soluble
drugs like
▫ griseofulvin
▫ indomethacin
▫ prednicolone
• Rapid release due to:
▫ Weak physical bonding between adsorbent-adsorbate
▫ Hydration
▫ Swelling of clay in the aqueous media

37. Comparison among solubilization techniques:
• Based on nature of drug molecules, site of action,
structure of molecules appropriate solubilization
technique is selected.
• Salt formation has wide spectra in solubility
enhancement from techniques which have been
discussed.

38. If any query then please feel free to
ask ………

39. References:
• Vemula VR, Venkateshwarlu L., Lingala s., solubility enhancement
technique. International Journal of Pharmaceutical sciences Review
and Research, Vol. 5, Nov–Dec 2010; Article-007,42.
• Pharmaceutics – The Science of Dosage Form Design Edited by
M.E. Aulton
• Encyclopedia of Pharmaceutical technology, Volume 3, Edited By
James Swarbrick, 2458-2477
• Encyclopedia of pharmaceutical technology, vol. -3, p. no. 337-344.
• Encyclopedia of pharmaceutical technology, vol. -14, page -: 207-
221.
• Physical Pharmacy, Third edition, By Alfred Martin
• The theory and practice of Industrial Pharmacy, By Leon Lachman
• Solubility and related properties by Kenneth c. James. Pg – : 253 –
271.
1. : 253 – 271.

40. Thanks for your kind attention..