2. CONTENTS
Solubilization.
Surfactant and its importance.
Temperature.
pH.
Cosolvency.
Solid dispersion.
β-Cyclodextrin drug dispersion technique.
References.
3. SOLUBILIZATION
Solubilization an important property of association
colloids in solution is an ability of the micelles to
increase the solubility of material that normally
insoluble or only slightly soluble in the dispersion
medium used this phenomenon known as
Solubilization.
4. SOLUBILITY ANALYSIS
Ionization constant (pKa)
Can be calculated by Henderson Hasselbach
equation-
For acidic drugs….pH= pKa+ log [ionized drug]/
[unionized drug]
For basic drugs…pH=pKa+ log [unionized drug]/
[ionized drug]
E.g. Aspirin (pKa-3.5)
5. PH SOLUBILITY PROFILE
The solubility of acidic or basic drug will show differences
in solubility with changes in pH.
The solubility of an acidic or basic drug depends on the pKa
of the ionizing functional group and the intrinsic solubilities
for both the ionized and unionized forms.
The relationship between solubility of the acidic drug and
pH is given by the equation
pH= pKa +log [Cs]/[Ca]
Where pKa =negative logarithm of the ionization constant
of the acid
[Cs]= molar concentration of the salt form in water
[Ca ] = molar concentration of free acid in water
6. Knowing the pKa , [Ca ],and pH total amt. of the
drug solubilized in the water can be calculated
Total solubility of the weak acid St is given by
St =[Ca] +[Cs]
equation for the weak bases is
St =[Cb] +[Cs]
7. COMMON ION EFFECT
If salt of weak acid or weak base is added to the
solution of acid or base resp. dissociation of acid or
base is diminished further.
E.g. the addition of sod. Acetate to sol. of acetic acid
suppresses the dissociation of acetic acid.
E.g. CH3COOH-----H+ +CH3COO
8. PARTITION COEFFICIENT
It is an ratio of Unionized drug distributed between
organic & aqueous phase at equilibrium.
Po/w = (Coil/Cwater)equilibrium
Partition Coefficient study is useful in the A.D.M.E
9. DISSOLUTION
It is controlled by several physicochemical properties- chemical
form, crystal habit, particle size, solubility, surface area and
wetting properties.
Noyes-Whitney eqn. dC / dt= AD (Cs-C)/hV
Where, dC = Dissolution rate
dT
A = surface area of dissolving solid
D = diffusion coefficient
H = diffusion layer thickness
C = solute concentration in the bulk medium
V = volume of dissolution medium
Cs = solute concentration in diffusion layer
10. GENERAL METHOD OF INCREASING THE
SOLUBILITY
Addition of co-solvent
E.g. Phenobarbitone (insoluble in water) add glycerol,
alcohol increased solubility
Addition of complexing agent
Described as shown in the equation –
n [D] +m [L] ↔[Dn: Lm ]s
where:-
[D]=conc. Of the drug in the solution
[L] =Conc. Of ligand in the solution
[Dn: Lm]=Conc. Of the drug ligand complex
E .g= solubility of benzocaine in caffeine
Apparent Solubility of Hexaethylmelamine is increased much
as 90 fold via complexation with the Gentisate ion
11. SURFACTANT
• Surfactants are wetting agents that lower the surface
• tension of a liquid, allowing easier spreading, and
• lower the interfacial tension between two liquids
Classification
Some commonly encountered surfactants of each type include:
• Ionic
– Anionic (based on sulfate, sulfonate or carboxylate anions)
• Sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, and other alkyl
sulfate salts
• Sodium laureth sulfate, also known as sodium lauryl ether sulfate (SLES)
– Cationic (based on quaternary ammonium cations)
• Cetyl trimethylammonium bromide (CTAB) a.k.a. hexadecyl trimethyl
ammonium bromide, and other alkyltrimethylammonium salts
• Cetylpyridinium chloride (CPC)
12. Zwitterionic (amphoteric)
Dodecyl betaine
Dodecyl dimethylamine oxide
Nonionic
Alkyl poly(ethylene oxide)
Copolymers of poly(ethylene oxide) and poly(propylene oxide)
(commercially called Poloxamers or Poloxamines)
13. HLB SCALE
Griffin an arbitrary scale of value to serve insure of
hydrophilic lipophilic balance of surface active
agent
The higher the HLB of the an agent, the more
hydrophilic it is
The spans, sorbitan ester are lipophilic and have
low HLB value (1.8-8.6)
Tweens, polyoxyethylene derivative of the spans
are hydrophilic and have high HLB value (9.6-16.7)
15. The HLB of non ionic surfactant whose only
hydrophilic portion is polyoxyethylene is
calculated using the formula
HLB = E/5
Where, E = Percentage weight of ethylene oxide
A number polyhydric alcohol fatty acid ester, such
as glyceryl monostearate may be estimated by
using the formula
HLB = 20( 1- S/A)
Where, S = saponification number of ester
A = acid number of fatty acid
16. The HLB of polyoxyethylene sorbitan monolaurate
(tween 20) for S = 45.5 and A = 276
HLB = 20( 1- 45.5/276) = 16.7
17. IMPORTANCE OF SURFACTANT
Surfactants play an important role in many
practical applications and products, including:
Detergents
Fabric softener
Emulsifiers
Paints
Adhesives
Inks
Soil remediation
Wetting
21. APPLICATION OF PH
Enhancing the solubility
Sodium salicylate ppt as salicylic acid when
acidified
Increasing stability
Vitamins are stable only with in a narrow pH
range
Improving purity
Insulin ppt from aqueous solution between pH
5.0 and 6.0
22. PH VALUES OF SOME PHARMACEUTICAL
PREPARATIONS
Drug name Formulation pH
Actified syrup 5-7.2
Benadryl Elixir 7.0
Orange syrup syrup 2.5-3.0
Vitamin B-
complex
Elixir 4.0-5.0
23. Optimizing biological activity
Pepsin as maximum activity at pH 1.5
Comforting the body
Storage of product
24. TEMPERATURE EFFECT
The heat of solution Hs represent the heat released
or absorbed when a mole of solute is dissolved in
larger quality of solvent. Most commonly solution
process is endothermic i.e. Hs is +ve & thus
increasing the temperature solution, thereby
solubility.
for such solute such as lithium chloride & other
hydrochloride salt that are ionised when dissolved,
the process is exothermic or Hs is –ve.
25. Ln S = -Hs[1/t]+c/R
where S= Molkar solubility at temp. T
R= gas constant.
26. COSOLVENCY
Introduction to Cosolvency
Definition
Techniques of Solubilization
Solubilization by Cosolvents
Some Practical Considerations
Conclusion
Introduction to Solid Dispersion
Definition
Carriers for Solid Dispersion
Methods of Preparation
Chracterization of Solid Dispersion system
Recent Development
β-Cyclodextrin Drug Dispersion system
Characteristics of β-Cyclodextrins
Physicochemical properties
Current Status
Conclusion
27. INTRODUCTION TO COSOLVENCY
Solubilization of poorly Soluble drug can be by
addition of some water miscible solvents in
which the drug has appreciable solubility.
This Solubility may be due to…..
Independent solubility of substance in each
solvent,
Disruption of Hydrophobic interactions of Water
molecules at the Nonpolar solute-water
interface.
28. DEFINITION
The Phenomenon of Increasing the solubility of
poorly soluble drug in combination with other
solvent/solvents is known as ‘Cosolvency’.
Techniques of Solubilization
Formation of Soluble salts,
Molecular complexes,
Cyclodextrin inclusion complexes,
Solubilization by Surfactants,
Solubilization by Cosolvents.
29. POLARITIES OF SOME COMMON
SOLVENT
Solubilization by Co-solvents :-
Polarity scales are used for this purpose, because
there is no absolute measure for the Polarity.
Measures of Polarity…
Dielectric constant(ε),Solubility parameter(δ), &
Surface tension(γ)
HLB scale is used to measure γ.
Macroscopic properties of solute & solvent are used
to measure ε,δ & γ.
30. POLARITIES OF SOME COMMON
SOLVENT
-: Solubilization by
Cosolvents :-
Polarity scales are used
for this purpose, because
there is no absolute
measure for the Polarity.
Measures of Polarity…
Dielectric
constant(ε),Solubility
parameter(δ), & Surface
tension(γ)
HLB scale is used to
measure γ.
Macroscopic properties
of solute & solvent are
used to measure ε,δ & γ.
Sr. no. Name Surface
Tension
(γ)
Solubilit
y
Paramete
r
(δ)
Dielectric
Constant
(ε)
1 Water 72.0 23.4 81.0
2 Glycerin 64.9 16.5 42.5
3 Ethylene
glycol
48.8 14.6 37.7
4 Furfural 43.5 12.5 41.9
5 Propylen
e glycol
37.1 12.6 32.0
31. NON-POLAR SOLUTES
Log PCO/C < Log PCO/w
If both are in Proportion then Partition coefficient in one partitioning system
is linearly related to the Partition coefficient in a similar system.
i.e. ζ = S Log PCO/w + T
where, ζ = solubilising power of the solvent,
S & T are the constants for each solvent.
PCO/w & PCO/C = Partition coefficient in Octanol-water & Octanol-
-cosolvent system
Yalkowsky et.al. shown that ζ is proportional to Log PC for a variety of
solute.
Hence ζ is dependent upon the solute polarity as measured by Log PCO/w &
on the cosolvent polarity as measured by S & T.
32. SEMI-POLAR SOLUTES
Semi-polar drugs has poor aqueous solubility due to strong
crystalline interactions & due to high activity coefficients in
water.
Paruta treated the solubility of semipolar drugs in mixed
aqueous system based on dielectric constant & martin used
regular solution theory.
In above approaches, the mixed solvent is treated as a linear
combination of water & cosolvent & max. in solubility curve
attained when the polarity of the drug…
PD=FCPC+FWPW
where, PD = polarity of Drug
f = fraction
P = polarity.
33. POLAR SOLUTES
These are more difficult to characterize than non-
polar & semi-polar solutes, b’coz the most polar
solutes can dissociate to some extent in aq.
Solution.
But polar solutes are nearly always crystalline &
high melting, they tend to be solubilise in water,
b’coz of their high affinity for water more than self
interactions of the crystalline lattice.
Addition of a less polar solvent to the water the
affinity of the solvent to solutes & thus solubility.
34. SOME PRACTICAL CONSIDERATIONS
Cosolvents have become the use of solubilising the
drugs for both IV & IM administration b’coz of
irritating effects of most surfactants & low toxicity
of cosolvents.
Frequently used cosolvents are…
Propylene glycol, ethanol, glycerine, PEG.
35. CONCLUSION
The increase in degree of solubilization of drug is
dependent upon Non-polarity of the drug & the
Non-polarity of cosolvent.
37. I NTRODUCTI ONTOSOLI DDI SPERSI ON
Various techniques for solubilization of
Drugs which has poor solubility in water…
Micronisation
Dispersion
Solvent Deposition
Complexation.
Solid Dispersion provides…
Particle size reduction &
Increased rates of Dissolution
38. DEFINITION
It is the Dispersion of one or more Active
ingredients in an inert carrier or matrix at Solid
state prepared by the Fusion or Melting solvent
method.
39. CARRIERS FOR SOLID DISPERSION
Characteristics :
a) Readily soluble in water,
b) Stable at processing temp.
c) Chemically & P’cologically inert.
Examples :
SUGARS :- Dextrose, Sorbitol etc.
ACIDS :- Citric Acid, Tartaric Acid etc.
POLYMERIC MATERIALS :- PEG 4000, PEG 6000,
Sodium Alginate etc.
41. MELTING METHOD:- (FUSION METHOD)
Physical mix. Of a Drug + Water soluble carrier, ∆ & cooled, solidify
in ice bath, Melt was poured on the ferrite or stainless steel plate,
cooled by flowing air or water on opposite side, solid mass is crushed
– pulverized – sieved.
Adv. :- a) Simplicity & economy
b) Supersaturation.
Disadv. :- Decomposition or Evaporation.
Remedial Measures :-
a) Use of sealed container,
b) Melting under vacuum or a blanket of inert gas like Nitrogen
42. SOLVENT METHOD:-
Dissolve physical mixture of two solid components in a
common solvent, Evaporation of solvent.
E.g.:- β-Carotenes – PVP, Griseofulvin – PVP etc.
Adv. :- Prevention of thermal decomposition
Disadv. :- a) Incomplete removal of solvent
b) Adverse effect of solvent on
chemical stability of drug,
c) Selection of common volatile
solvents & Possible polymorphic
changes.
43. MELTING & SOLVENT METHOD:-
The drug is first Dissolve in solvent then the solution
incorporated directly into the melt of the carrier.
Adv. :- It has both melting as well as
solvent method.
Disadv.:- It is limited to drugs with low
therapeutic dose.
44. VARIOUS SYSTEMS OF SOLID DISPERSION
Simple Eutectic mixtures
Solid Solutions
a) Continuous Solid solution
b) Discontinuous Solid solution
- Substitutional Solid solution
- Interstitial Solid solution
Glass solution & Glass Suspension
Amorphous precipitation in a crystalline carrier
Compound or complex formation betn drug &
carriers.
46. RECENT DEVELOPMENT
Because of Difficulty to scale up for the manufacture of solid
dispersion by Pulverization, Sieving, Mixing with relatively large
amt. of Excipients & encapsulation in to hard gelatin capsules or
compressing in to Tablet,in recent yrs. Surface active, self
emulsifying carriers & devp. of technologies which are used to
encapsulate solid dispersion directly in to Hard gelatin capsule as
melts are Developed.
E.g. a) Poloxamer 188 as a carrier for Ibuprofen,
b) Poloxamer 407 as a carrier for Nifedipine,
c) PEG, Myri 2, Eudragit E100 as a carrier for
Indomethacin.
47. Β-CYCLODEXTRIN DRUG DISPERSION
SYSTEM
Cyclodextrins are cyclic, non-reducing, water
soluble oligosaccharides.
Cyclodextrin has beneficial effects on solubility,
dissolution rate, chemical stability & absorption
rate of a drug.
They are available in three forms…
- α,β & γ Cyclodextrins consisting of six, seven &
eight D-glucopyranose units.
48. CHARACTERISTICS OF Β-CYCLODEXTRIN
Sr. no. Characteristics β-Cyclodextrin
01. No. of Glucose units 7
02. Molecular wt. 1135
03. Solubility in water (g/100ml)
at RT
1.85
04. Optical rotation 162 + 0.5
05. Cavity diameter 6.0 + 6.5
07. Diameter of outer periphery
(A0)
15.4 + 0.4
08. Approx. volume of cavity
(A0)
262
49. PHYSICOCHEMICAL PROPERTIES
It has cylindrical shape with a central axial cavity.
All secondary hydroxyl groups are located on one side of
the molecule, while all primary hydroxyl groups are on
the other hand.
The lining of the internal cavity is formed by the oxygen-
bridge atoms, which makes the cavity slightly aploar.
Marketed Solid formulations:-
Piroxicam- β-CD tablets & suppositories.
Benexate- β-CD Capsules.
Omeprazole- β-CD Capsule.
50. CURRENT STATUS
It is not yet considered as standard inactive
ingredients in p’ceuticals due to the uncertain
regulatory acceptance of a formulation containing
non-standard inactive ingredient.
25 CD based products are available currently in the
Market.
51. CONCLUSION
Use of CD’s is a practical way to improve the
physicochemical & p’ceutical properties of Drug
molecules.
Play an Imp. Role in the development of formulations
due to their effects on Solubility & absorption of
Drug.
They are safe & non-toxic both orally & parenterally.
They enhances the solubility,Dissolution rate &
bioavailability to improve chemical & physical
stability
Reduces unpleasant side effects & bitter taste & to
achieve sustained action.
52. REFERENCES
The Theory and Practice of Industrial Pharmacy by
Leon Lachman and H.A.Lieberman, 3rd and 4th
edition.
Text book of Physical Pharmacy by Alfred Martin,
Varghese publication.
Text book of Pharmaceutical Dosage Forms by
H.A.Lieberman and Leon Lachman.
Text book of Modern Pharmaceutics by Gilbert
&Banker.
Text book of pharmaceutical practice by M .Aulton.
Pharmaceutical dosage forms –parenteral
medications ,volume 1by Kenneth E. Avis ,Leon
Lachmann,Herbert A Liebermann,Marcel Dekker
inc, 270 Madison Avenue ,New York
53. Pharmaceutical dosage forms –parenteral
medications ,volume 1by Kenneth E. Avis ,Leon
Lachmann,Herbert A Liebermann,Marcel Dekker
inc, 270 Madison Avenue ,New York
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