1. PREFORMULATION
By:-
Saiesh P.Phaldesai
1st year M-Pharma
Pharmaceutics
Srinivas college of pharmacy
Mangalore

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)

14. HLB SCALE
 Most antifoaming agents
 W/O Emulsifying agents
 Wetting and Spreading agents


 O/W Emulsifying agents
 Detergents and Solubilizing agents
0
3
6
9
12
15
18

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

18.  Ski Wax
 Snowboard Wax
 Foaming
 Defoaming
 Laxatives
 Agrochemical formulations
 Herbicides
 Insecticides
 Quantum dot coating
 Biocides (Sanitizers)
 Hair Conditioners (after shampoo)
 Spermicide (Nonoxynol 9)

19. PH
 pH may be defined as negative logarithum of
hydrogen ion concentration

20. PH SCALE
0
Acidic
7 Neutral
14 basic

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.

36. SOLID DISPERSION

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.

40. METHODS OF PREPARATION
 Melting method
 Solvent method
 Melting & Solvent method.

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.

45. CHARACTERIZATION OF SOLID DISPERSION
SYSTEM
 Thin layer Chromatography
 Spectroscopic Method
 Solubility determination
 Dissolution rate method
 Microscopic Method
 Thermal analysis
 Cooling curve Method
 Thaw melt Method
 Thermo-Microscopic Method
 Differential Thermal Analysis
 Zone Melting Method
 X-ray diffraction Method

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
 Google( online articles )
 www.ijps.com