This document discusses solubility of drugs from the perspectives of a medicinal chemist and pharmaceutical scientist. From the medicinal chemist perspective, it discusses Lipinski's rule of five for predicting solubility and permeability. It also discusses methods for calculating absorption parameters and predicting aqueous solubility, such as the Moriguchi method for calculating logP. From the pharmaceutical scientist perspective, it outlines various techniques for enhancing drug solubility, including particle size reduction through micronization or nanosuspension, modifying crystal habit through polymorphs or complexes, and chemical modifications through prodrugs or buffer systems. Overall, the document provides an overview of key considerations and approaches for optimizing drug solubility from different scientific viewpoints.

1. 1. Introduction
2. Medicinal chemist prospective
3. Pharmaceutical scientist prospective
4. Conclusion
1
Solubility of drugs in the perspectives of
Medicinal Chemist and Pharmaceutical Scientist
Sultan Ullah
PhD Scholar
Synthetic medicinal chemistry lab,
College of pharmacy ,PNU.

2. • 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 candidates have both high
solubility and permeability.
• Nearly 40% of the new chemical entities currently being
discovered are poorly water soluble.
• More than one-third of the drugs listed in the U.S.
Pharmacopoeia fall into the poorly water-soluble or water-
insoluble categories.
• Low aqueous solubility is the major problem encountered
with formulation development of new chemical entities.
• Any drug to be absorbed must be present in the form of an
aqueous solution at the site of absorption.
Biopharmaceutical classification system
1. Introduction
2

3. 2. Medicinal chemist prospective
The 'rule of 5’ states that: poor absorption or
permeation are more likely when:
There are more than 5 H-bond donors
(expressed as the sum of OHs and NHs);
The MWT is over 500;
The Log P is over 5 (or MLogP is over 4.15);
There are more than 10 H-bond acceptors
(expressed as the sum of Ns and Os);
Compound classes that are substrates for
biological transporters are exceptions to the
rule. These orally active therapeutic classes
outside the ‘rule of 5’ are: antibiotics,
antifungals, vitamins and cardiac glycosides.
3
2.1 Lipinski Rule of Five

4. • From the rule of five here are four parameters that should be globally associated with
solubility and permeability;
• 1. molecular weight;
• 2. Log P;
• 3. The number of H-bond donors
• 4. The number of H-bond acceptors.
• Large molecular weight ,lipid bilayer affect permeability.
• Less orally active
• An excessive number of hydrogen bond donor groups impairs permeability
across a membrane bi-layer
• At the USAN library there is a sharp cutoff in the number of compounds
containing more than 5 OHs and NHs.
• Many hydrogen bond acceptor groups also hinder permeability across a
membrane bi-layer
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2. Medicinal chemist prospective
2.1. Lipinski Rule of Five

5. 2.2. Calculation of Absorption Parameters
• For a good absorption of drugs, the four parameters mentioned in Lipinski rule of five are
calculated by the following methods.
1. Over all approach
• The four parameters used for the prediction of potential absorption problems can be easily
calculated with any computer and a programming language that supports or facilitates the
analysis of molecular topology.
• MDL's sequence and MEDIT languages for MACCS have since successfully ported the
algorithms to Tripos' SPL and MDL's ISIS PL languages in Pfizer.
• The parameters of molecular weight and sum of nitrogen and oxygen atoms are very
simple to calculate and require no further discussion.
• Likewise, the calculation of the number of hydrogen-bond acceptors is simply the number
of nitrogen and oxygen atoms attached to at least one hydrogen atom in their neutral
state.
5
2. Medicinal chemist prospective

6. 2.2. Calculation of absorption parameters
2. MLog P. Log P by the method of Moriguchi
The method begins with a straightforward counting of
• Lipophilic atoms (all carbons and halogens with a multiplier rule for normalizing their contributions) and
• Hydrophilic atoms (all nitrogen and oxygen atoms).
• Using a collection of 1230 compounds, Moriguchi et al. found that these two parameters alone account for 73% of the variance in the
experimental log Ps. When a ‘saturation correction’ is applied by raising the lipophilic parameter value to the 0.6 power and the hydrophilic
parameter to the 0.9 power, the regression model accounted for 75% of the variance.
• The Moriguchi method then applies 11 correction factors, four that increase the hydrophobicity and seven that increase the lipophilicity, and
the final equation accounts for 91% of the variance in the experimental log Ps of the 1230 compounds.
• The correction factors that increase hydrophobicity are:
• 1. UB, the number of unsaturated bonds except for those in nitro groups. Aromatic compounds like benzene
are analyzed as having alternating single and double bonds so a benzene ring has 3 double bonds for the UB
correction factor, naphthalene has a value of 5;
• 2. AMP, the correction factor for amphoteric compounds where each occurrence of an alpha amino acid
structure adds 1.0 to the AMP parameter, while each amino benzoic acid and each pyridine carboxylic acid
occurrence adds 0.5;
• 3. RNG, a dummy variable which has the value of 1.0 if the compound has any rings other than benzene or
benzene condensed with other aromatic, hetero-aromatic, or hydrocarbon rings;
• 4. QN, the number of quaternary nitrogen atoms (if the nitrogen is part of an N-oxide, only 0.5 is added).
6
2. Medicinal chemist prospective

7. 2.2. Calculation of absorption parameters
• The correction factors that increase lipophilicity
1. PRX a proximity correction factor for nitrogen and oxygen atoms that are close to one another topologically.
For each two atoms directly bonded to each other, add 2.0 and for each two atoms connected via a carbon,
sulfur, or phosphorus atom, add 1.0 unless one of the two bonds connecting the two atoms is a double bond, in
which case, according to some examples in the papers, you must add 2.0. In addition, for each carboxamide
group, we add an extra 1.0 and for each sulfonamide group, we add 2.0;
2. HB, a dummy variable which is set to 1.0 if there are any structural features that will create an internal
hydrogen bond. We limited our programs to search for just the examples given in the Moriguchi paper as it is
hard to determine how strong a hydrogen bond has to be to affect lipophilicity;
3. POL, the number of heteroatoms connected to an aromatic ring by just one bond or the number of carbon
atoms attached to two or more heteroatoms which are also attached to an aromatic ring by just one bond;
4. ALK, a dummy parameter that is set to 1.0 if the molecule contains only carbon and hydrogen atoms and no
more than one double bond;
5. NO2, the number of nitro groups in the molecule;
6. NCS, a variable that adds 1.0 for each isothiocyanate group and 0.5 for each thiocyanate group;
7. BLM, a dummy parameter whose value is 1.0 if there is a beta lactam ring in the molecule.
7
2. Medicinal chemist prospective

8. 2.3. Prediction of aqueous thermodynamic solubility
• The prediction of the aqueous solubility of drug candidates is of paramount
importance in assisting the discovery, as well as the development, of new
drug entities. Low aqueous solubility even in the presence of a good
permeation rate results in low absorption. Conversely, a compound with
high aqueous solubility might be well absorbed, even if it possesses a
moderate or low permeation rate
• Formulation efforts can help in addressing these problems, but there are
severe limitations to the absorption enhancement that can be realistically
achieved.
• Obviously, a method for predicting solubility of drug candidates at an early
stage of discovery would have a great impact on the overall discovery and
development process.
8
2. Medicinal chemist prospective

9. 2.3. Prediction of aqueous thermodynamic solubility
• Aqueous solubility of a given molecule is the result of a complex interplay
of several factors ranging from the hydrogen-bond donor and acceptor
properties of the molecule and of water, to the energetic cost of disrupting
the crystal lattice of the solid in order to bring it into solution
(‘fluidization’).
• Thus, any method which would aim at predicting the aqueous solubility of
a given molecule would have to take into account a more comprehensive
‘description’ of the molecule as the outcome of the complex interplay of
factors.
• None of the presently available methods can truly be exploited for a
relatively accurate prediction of solubility, if the target of the prediction is
the solubility of complex pharmaceutical drug candidates.
9
2. Medicinal chemist prospective

10. 2.3. Prediction of aqueous thermodynamic solubility
• The three basic quantities governing the solubility (S) of a given solid solute:
S = f(Crystal Packing Energy + Cavitation Energy + Solvation Energy)
• In this equation, the crystal packing energy is a (endoergic) term which accounts for
energy necessary to disrupt the crystal packing and to bring isolated molecules in gas
phases, i.e. its enthalpy of sublimation.
• The cavitation energy is a (endoergic) term which accounts for the energy necessary to
disrupt water (structured by its hydrogen bonds) and to create a cavity into which to host
the solute molecule.
• The solvation energy might be defined as the sum (exoergic term) of favorable
interactions between the solvent and the solute.
• Determination or estimation of melting point or, better, of their enthalpy of sublimation
are major hurdles in the prediction of aqueous solubilities of crystalline solids products.
• At present no accurate and efficient method is available to predict these two quantities
for the relatively complex molecules which are encountered in the pharmaceutical
research.
10
2. Medicinal chemist prospective

11. 2.3.Prediction of aqueous thermodynamic solubility
• The following methods are designed by some scientist to predict the solubility of drugs.
i. LSERs and TLSER methods
ii. LogP and AQUAFAC methods
iii. Other calculation methods
i. LSERs and TLSER methods
Linear Solvation Energy Relationships (LSERs), based upon solvatochromic parameters, have the advantage of a
good theoretical background and offer a correlation between several molecular properties, and a solute
property, SP. Most notably, the work of Abraham et al. has generated an equation of the general type:
LogSP = c + rR2 + aΣαH
2 + bΣβH
2 + sπH
2 + nVx
where c is a constant, R2 is an excess molar refractivity, Σα2H and Σβ2H are the (summation or ‘effective’) solute hydrogen-bond acidity and basicity,
respectively, π2H is the solute dipolarity-polarizability and Vx is McGowan's characteristic volume.
Disadvantages of this method:
Not suitable for complex multi-functional molecules such as drug candidates, especially if they are capable of intra-molecular
hydrogen bonding, as is often the case
11
2. Medicinal chemist prospective

12. 2.3. Prediction of aqueous thermodynamic solubility
Kamlet equations describing the solubility of aromatic solutes including polycyclic and
chlorinated aromatic hydrocarbons. In these equations a term accounting for the crystal
packing energy was introduced.
log Sw(aromatics) – (0.24−5.28V1/ 100) + 4.03βm +1.53αm−0.0099 (m.p.−25)
Disadvantage: not useful in close structural analogs where a large variation in melting
points (>100 °C) is not expected (as might often be the case) and the ‘solution behavior’
could be estimated by solvatochromic parameters.
The equations stemming from computed values have been termed TLSERs (Theoretical
Linear Solvation Energy Relationships).
12
2. Medicinal chemist prospective

13. 2.3. Prediction of aqueous thermodynamic solubility
ii. LogP and AQUAFAC methods
Yalkowski, who using LogP (the logarithm of the octanol/water partition coefficient) and a term
describing the energetic cost of the crystal and predicted the solubility of halogenated aromatic and
polycyclic halogenated aromatic hydrocarbons. The general solubility equation, for organic non-
electrolytes is reported below.
log Spred = −ΔSm(m.p.−25/ 1364) −log P + 0.80
In this equation, ΔSm is the entropy of melting and m.p. is the melting point in °C. The
signs of the two terms considered are physically reasonable, since an increase in either the
first term (higher crystal packing energy) or in LogP (more lipophilic compound), would
cause a decrease in the observed (molar) solubility Sm.
The activity coefficient is best achieved by using the LogP method. Many computational
methods are indeed available to address the prediction of LogP and the aqueous solubility
of complex molecules. A well known and widely used program to predict LogP values is
CLogP which uses a group-contribution approach to yield a LogP value.
13
2. Medicinal chemist prospective

14. 2.3. Prediction of aqueous thermodynamic solubility
Yalkowski and colleagues discussed an improvement of the AQUAFAC (AQUeous Functional group
Activity Coefficients) fragmental constant method. In this work, the authors describe a correlation
between the sum of fragmental constants of a given molecule and the activity coefficient, defined
as a measure of the non-ideality of the solution.
log Spred = [−ΔSm(m.p.−25)/1364 ]−Σniqi
where qi is the group contribution of the ith group and ni is the number of times the ith group appears in the molecule. The
negative sign ofthe second term stems from the fact that the constant of polar groups (e.g. OH=−1.81) has a negative sign
and a net negative sign of the summation of contributors would yield an overall positive contribution to solubility
Disadvantage: limited to molecule containing relatively simple functional groups
iii. Other calculation methods
Bodor and Huang [49] and Nelson and Jurs [50] have reported methods based entirely on calculated
geometric, electronic and topological descriptors, for a series of relatively simple liquid and solid
solutes.
14
2. Medicinal chemist prospective

15. 3. Pharmaceutical scientist prospective
I. Physical Modifications
A. Particle size reduction
1.Micronization
2.Nanosuspension
3.Sonocrystalisation
4.Supercritical fluid process
B. Modification of the crystal habit
1.Polymorphs
2.Pseudopolymorphs
C. Drug dispersion in carriers
1. Eutectic mixtures
2. Solid dispersions
3. Solid solutions
D. Complexation
Use of complexing agents
E. Solubilization by surfactants
Microemulsions
15
II. Chemical Modifications
1. Change in the pH
2. Use of buffer
3. Derivatization
III. Other methods
1.co-crystallisation
2. co-solvency
3.Hydrotrophy
4.Solubilizing agents
5.Selective adsorption on insoluble carrier
6.Solvent deposition
7.Using soluble prodrug
8.Functional polymer technology
9.Precipitation Porous
10.microparticle technology
11.Nanotechnology approaches
Solubility enhancement techniques

16. A. Particle size reduction:
Particle size reduction can be achieved by
a. Micronization
b. nanosuspension
c. Sonocrystalisation
d.Supercritical fluid process
1. Micronization:
• Micronization increases the dissolution rate of drugs through increased surface area.
• Micronization of drugs is done by milling techniques using jet mill, rotor stator colloid mills etc.
• Micronization is not suitable for drugs having a high dose number because it does not change the
saturation solubility of the drug .
• The process involves reducing the size of the solid drug particles to 1 to 10 microns commonly by spray
drying or by use of attrition methods. The process is also called micro-milling.
16

17. 2. Nanosuspension :
Nanosuspensions are sub-micron colloidal dispersion of pure particles
of the drug, which are stabilized by surfactants.
Nanosuspension technology is used for efficient delivery of hydrophobic
drugs . The particle size distribution of the solid particles in nanosuspensions
is usually less than one micron with an average particle size ranging between
200 and 600 nm.
Increased dissolution rate due to larger surface area exposed.
Eg., Nanosuspension approach has been employed drugs like paclitaxel,
tarazepide, amphotericin B which are still on research stage.
Advantage :

18. 3.Sonocrystallisation :
Particle size reduction on the basis of crystallisation by using ultrasound is
Sonocrystallisation . Sonocrystallisation utilizes ultrasound power for
inducing crystallisation . It not only enhances the nucleation rate but also an
effective means of size reduction and controlling size distribution of the
active pharmaceutical ingredients. Most applications use ultrasound in the
range 20 kHz-5 MHz.
4. Supercritical fluid process :
• A supercritical fluids are dense non-condensable fluid whose temperature and
pressure are greater than its critical temperature ( Tc ) and critical pressure ( Tp )
allowing it to assume the properties of both a liquid and a gas.
• Through manipulation of the pressure of SCFs, the favourable characteristics of
gases – high diffusivity, low viscosity and low surface tension may be imparted
upon the liquids to precisely control the solubilisation of a drug with a
supercritical fluid. 18

19. • Once the drug particles are solubilised within SCFs, they may be
recrystalised at greatly reduced particle sizes.
• A SCF process allows micronisation of drug particles within
narrow range of particle size, often to sub-micron levels.
19

20. B. Modification of the crystal habit:
One polymorphs form can No reversible transition
change reversibly into another is possible.
at a definite transition temperature
below the melting point.
• Metastable forms are associated with higher energy and thus higher solubility.
Similarly the amorphous form of drug is always more suited than crystalline form due
to higher energy associated and increased surface area.
• The anhydrous form of a drug has greater solubility than the hydrates. This is because
the hydrates are already in interaction
20
Polymorphs
MonotropicEnantiotropic

21. with water and therefore have less energy for crystal
breakup in comparison to the anhydrates.
• They have greater aqueous solubility than the crystalline
forms because they require less energy to transfer a
molecule into solvent. Thus, the order for dissolution of
different solid forms of drug is
• Melting followed by a rapid cooling or recrystallization from
different solvents can produce metastable forms of a drug.
Amorphous > metastable polymorph > stable polymorph
21

22. 22
C. Drug dispersion in carriers:
The term “solid dispersions” refers to the dispersion of one or
more active ingredients in an inert carrier in a solid state, frequently
prepared by the
1.
• Hot melt mehod
2.
• Solvent evaporation method
3.
• Hot melt extrusion method

23. 23
1. Hot melt method :
Drug + vehicle (m.p low, organic solvent – insoluble)
(heating)
Melting
.
Freezing quickly
Dosage forms
Suitable to drugs and vehicles with promising heat stability.
A molecular
dispersion can be
achieved or not,
depends on the
degree of
supersaturation and
rate of cooling used
in the process.
Important
requisites :
1. Miscibility of the
drug & carrier
in the molten
form,
2. Thermostability
of the drug &
carrier.
Suitable to drugs and vehicles with promising heat stability.

24. 24
2. Solvent evaporation method:
Drug + vehicle ( both soluble in solvent)
organic solvent
solution
evaporate the solvent
coprecipitates
dosage forms
suitable to drugs with volatility or poor stability
Temperatures used
for solvent
evaporation
generally lie in the
range 23-65°C.
The solvent
evaporation can
be done by spray
drying or freeze
drying.

25. 25
3.Hot-melt Extrusion:
Hot melt extrusion of miscible components results in
amorphous solid solution formation, whereas extrusion of an
immiscible component leads to amorphous drug dispersed in
crystalline excipient. The process has been useful in the
preparation of solid dispersions in a single step.

26. 26

27. 27
D. Complexation :
Complexation is the reversible association between
two or more molecules to form a nonbonded entity with a well
defined stoichiometry . Complexation relies on relatively weak
forces such as van-derwaal forces, hydrogen bonding and
hydrophobic interactions.
Inclusion complexation : These are formed by
the insertion of the nonpolar molecule or the
nonpolar region of one molecule into the cavity
of another molecule or group of molecules. The
most commonly used host molecules are
cyclodextrins . Cyclodextrins are non- reducing,
crystalline , water soluble, cyclic,
oligosaccharides. Cyclodextrins consist of
glucose monomers arranged in a donut shape
ring.
Inclusion complexation:
CYCLODEXTRIN
Hydrphobic
Hydrophillic

28. 28
The surface of the cyclodextrin molecules makes them water
soluble, but the hydrophobic cavity provides a microenvironment
for appropriately sized non-polar molecules. Based on the structure
and properties of drug molecule it can form 1:1 or 1:2 drug
cyclodextrin complex. Three naturally occurring CDs are α
Cyclodextrin, β Cyclodextrin, and γ Cyclodextrin.

29. 29
Organic drug + water → Squeezed out by strong water-water interaction
force.
Forms aggregates
Reduces the contact b/w nonpolar hydrocarbon moieties & the polar
water molecule
Large nonpolar regions
Opposed by entropy
Random arrangement
Complexes stached can be homogeneous or mixed
Self association complexation
Staching complexation
Eg .,
Nicotinamide,
Anthracene,
Caffeine,
Theobromine.

30. 30
E. Solubilization by surfactants:
Surfactants are molecules with
distinct polar and nonpolar regions.
Most surfactants consist of a
hydrocarbon segment connected to a
polar group. The polar group can be
anionic, cationic, zwitter ionic or
nonionic. The presence of surfactants
may lower the surface tension and increase the solubility of the
drug within an organic solvent .
Microemulsion : A microemulsion is a four-component system
composed of external phase, internal phase, surfactant and co
surfactant . The addition of surfactant, which is predominately
soluble in the internal phase unlike the co surfactant , results in the
formation of an optically clear, isotropic, thermodynamically stable
emulsion. It is termed as microemulsion because of the internal
phase is <0.1 micron droplet diameter.

31. 31
The surfactant and the co surfactant alternate each other and
form a mixed film at the interface, which contributes to the
stability of the microemulsion .
Non-ionic surfactants, such as Tweens ( polysorbates ) and Labrafil
( polyoxyethylated oleic glycerides ), with high hyrophile-lipophile
balances are often used to ensure immediate formation of oil-in-
water droplets during production.
Advantages :
 Ease of preparation due to spontaneous formation.
 Thermodynamic stability,
transparent and elegant appearance,
enhanced penetration through the biological membranes,
increased bioavailability and
less inter- and intra-individual variability in drug
pharmacokinetics.

32. 32
II. CHEMICAL MODIFICATIONS
1)By change of pH:
For organic solutes that are ionizable, changing
the pH of the system is the simplest and most effective means of
increasing aqueous solubility .
LOWER pH UNIONISED FORM INSOLUBLE PPT
HIGHER pH IONISED FORM MORE SOLUBLE DRUG
Lower pH Ionized form More soluble drug
Higher pH UNIONISED FORM INSOLUBLE PPT

33. 33
3) Derivatization : It is a technique used in chemistry which
transforms a chemical compound into a product of similar
chemical structure, called derivative. Derivatives have different
solubility as that of adduct. It is used for quantification of adduct
formation of esters and amides via acyl chlorides.
2) Use of buffer: Buffer maintains the pH of the solution
overtime and it reduces or eliminate the potential for precipitation
upon dilution. On dilution pH alteration occurs that decrease
solubility . Change of pH by 1 fold increase solubility by 10 fold If it
changes by one pH unit ,that decrease ionization of the drug and
solubility decreases by 10 fold.

34. 34
1.Co-crystallization:
A co-crystal may be defined as a crystalline material
that consists of two or more molecular species held together by
non-covalent forces.
• Co-crystals are more stable, particularly as the co-crystallizing
agents are solids at room temperature.
• Co-crystals can be prepared by evaporation of a heteromeric
solution or by grinding the components together.
• Another technique for the preparation of co-crystals includes
sublimation, growth from the melt, and slurry preparation.
•Only three of the co-crystallizing agents are classified as generally
recognised as safe (GRAS) it includes saccharin, nicotinamide and
acetic acid limiting the pharmaceutical applications.
III. OTHER METHODS.

35. 35
2. Cosolvency : Cosolvents are prepared by mixing miscible or
partially miscible solvents. Weak electrolytes and nonpolar
molecules have poor water solubility and it can be improved by
altering polarity of the solvent. It is well-known that the addition
of an organic cosolvent to water can dramatically change the
solubility of drugs. Cosolvent system works by reducing the
interfacial tension between the aqueous solution and hydrophobic
solute.
SOME PERANTRALPRODUCT THAT CONTAIN
COSOLVENT
1.Diazepam - 10% ethanol + propylene glycol
2.Digoxin - 10% ethanol + propylene glycol
Aquous solvent - Etahnol, sorbitol, glycerin,
propylene glycol.
Non aquous solvent - glycerol dimethyl ketal,
glycerol formal, glycofurol,
dimethyl acetamide.

36. 36
3. Hydrotrophy : Hydrotrophy designate the increase in solubility
in water due to the presence of large amount of additives. The
mechanism by which it improves solubility is more closely related
to complexation involving a weak interaction between the
hydrotrophic agents (sodium benzoate, sodium acetate, sodium
alginate, and urea).

37. 37
5. Selective adsorption on insoluble carriers: A highly active
adsorbent such as inorganic clays like Bentonite can enhance the
dissolution rate of poorly water-soluble drugs such as griseofulvin,
indomethacin and prednisone by maintaining the concentration
gradient at its maximum. 2 reasons suggested for rapid release of
drugs from the surface of clays :-
1. weak physical bonding between adsorbate and adsorbent.
2. hydration and swelling of the clay in the aqueous media.
4. Solubilizing agents: The solubility of poorly soluble drug can also
be improved by various solubilizing materials. PEG 400 is improving
the solubility of hydrochlorthiazide85. Modified gum karaya (MGK),
a recently developed excipient was evaluated as carrier for
dissolution enhancement of poorly soluble drug, nimodipine .

38. 38
7. Use of soluble prodrug :
Prodrug stratergy involves the
incorporation of polar or
ionizable moiety into the
parent compound to improve
aqueous solubility. Example :
prodrug of established drugs
has been successfully used to
improve water solubility of
corticosteroids
benzodiazepines.
6. Solvent deposition: In this method, the poorly aqueous soluble
drug such as Nifedipine is dissolved in an organic solvent like alcohol
and deposited on an inert , hydrophilic, solid matrix such as starch or
microcrystalline cellulose and evaporation of solvent is done.

39. 39
9. Precipitation: In this method, the poorly aqueous soluble drug
such as cyclosporine is dissolved in a suitable organic solvent
followed by its rapid mixing with a non-solvent to effect
precipitation of drug in nano size particles. The product so
prepared is also called as hydrosol.
10. Porous microparticle technology: The poorly water soluble drug
is embedded in a microparticle having a porous, water soluble,
sponge like matrix, dissolves wetting the drug and leaving a
suspension of rapidly dissolving drug particles. These drug particles
provide large surface area for increased dissolution rate . This is the
core technology applied as HDDS.
8. Functional Polymer Technology : Functional polymer enhances
the dissolution rate of poorly soluble drugs by avoiding the lattice
energy of the drug crystal, which is the main barrier to rapid
dissolution in aqueous media. The dissolution rate of poorly
soluble , ionizable drug like cationic, anionic and amphoteric
actives can be enhanced by this technology. Applied to heat
sensitive materials and oils also.

40. 40
11. Nanotechnology approaches : For many new chemical entities
of very low solubility ,oral bioavailability enhancement by
micronization is not sufficient because micronized product has a
tendency of agglomeration, which leads to decreased effective
surface area for dissolution . Nanotechnology refers broadly to
the study and use of materials and structures at the nanoscale
level of approximately 100 nanometers (nm) or less .
NANOCRYSTAL: Size: 1-1000 nm Crystalline material with
dimensions measured in nanometers. There are two distinct
methods used for producing nanocrystals . 1 . bottom-up. 2. top-
down . The top-down methods (i.e. Milling and High pressure
homogenization ) start milling down from macroscopic level, e.g.
from a powder that is micron sized. In bottom-up methods (i.e.
Precipitation and Cryo -vacuum method), nanoscale materials are
chemically composed from atomic and molecular components.

41. 41
NanoMorph :
• The NanoMorph technology is to convert drug substances with
low water-solubility from a coarse crystalline state into amorphous
nanoparticles .
•A suspension of drug substance in solvent is fed into a chamber,
where it is rapidly mixed with another solvent. Immediately the
drug substance suspension is converted into a true molecular
solution. The admixture of an aqueous solution of a polymer
induces precipitation of the drug substance. The polymer keeps the
drug substance particles in their nanoparticulate state and prevents
them from aggregation or growth. Using this technology the coarse
crystalline drug substances are transformed into a nanodispersed
amorphous state, without any physical milling or grinding
procedures. It leads to the preparation of amorphous nanoparticles
.

42. • Preformulation solubility studies focus on drug-solvent systems
that could occur during the delivery of a drug candidate.
• Solubility is important for preparing solution which can be
injected IV or IM OR drugs, which are unstable on contact with
solvent.
• Analytical methods that are useful for solubility measurement
include HPLC, GC, UV, and Fluoresence spectroscopy.
• Preformulation solubility studies usually include determinations
of pka, temperature dependence, pH solubility profile,
solubilization mechanisms, and rate of dissolution.
42

43. pKa Determinations
Many drugs are either weakly acidic or basic compounds. In
solution depending on the ph values, they exist as ionised or
unionised species.
The unionised species are liquid soluble and hence more readily
absorbed. The gastrointestinal absorption of weakly acidic or basic
drugs depends on factors such as:
- fraction of drugs in unionised form,
- pH at the site of absorption,
- ionisation constant,
- lipid solubility of the unionised species.
The relative concentration of ionised and unionised form of
weakly acidic or basic drug in a solution can be calculated using
Henderson Hesselbalch equation.
43

44. • The stomach conditions are acidic in nature ranging in pH from
1-3, weakly acidic drugs are preferentially absorbed from the
stomach. The ph of intestinal fluids ranges from 5-8, weakly
basic compounds are absorbed from the intestine.
44

45. 45
Methods of determination of pKa :
1. Detection of spectral shifts by UV spectroscopy at various pH.
Advantage: Dilute aqueous solutions can be analyzed by this
method.
2. Potentiometric titration
Advantage:
Maximum sensitivity for compounds with pKa in the range of 3
to 10.
Disadvantage:
This method is unsuccessful for candidates where precipitation
of the unionized forms occurs during titration. To prevent
precipitation a co-solvent e.g. methanol or dimethylsulfoxide
(DMSO) can be incorporated.

46. Effect of temperature
• The heat of solution, ΔHS, represents the heat released or absorbed when a mole
of solute is dissolved in a large quantity of solvent. Most commonly, the solution
process is endothermic, or ΔHs is positive, and thus increasing the solution
temperature increases the drug solubility.
• Heat of solution can be determined from solubility values for saturated solutions
equilibrated at controlled temperatures over the range of interest.
• Solvent systems involving cosolvents, micelles, and complexation have very
different heats of solution in comparison to water.
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47. Partition coefficient
• The partition coefficient is defined as the ratio of un-ionised drug
distributed between the organic and aqueous phases at
equilibrium.
• Partition Coefficient (oil/ water) is a measure of a drug’s
lipophilicity and an indication of its ability to cross cell membranes.
• Although partition coefficient data alone does not provide
understanding of in vivo absorption, it does provide a means of
characterizing the lipophilic/ hydrophilic nature of the drug.
• If P much greater than 1 are classified as lipophilic, whereas those
with partition coefficient much less than 1 are indicative of a
hydrophilic drug.
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PO/W = (COIL/ CWATER)equilibrium

48. Dissolution
• Dissolution of a drug particle is controlled by several
physicochemical properties, including chemical form, crystal habit,
particle size, solubility, surface area, and wetting properties.
• The dissolution rate of a drug substance in which surface area is
constant during dissolution is described by the modified Noyes-
Whitney equation:
where D is the diffusion coefficient,
h – diffusion layer at the solid-liquid interface,
A – surface area of drug exposed to dissolution media,
v – volume of media,
CS – concentration of a saturated solution of the solute,
C – concentration of drug in solution at time t
dc/dt – dissolution rate. 48
dc/dt = DA (CS – C) / hv

49. 4. Conclusion
• Currently, only approximate estimates of the solubility of multifunctional and conformationally
flexible drug candidates are possible and these need to be supported by physical measurements
which provide experimental ‘feedback’ on analogs in a particular class of compounds.
• A priori solubility estimation methods like Bodor's multi-parameter equation are the current best
choice, but some of the required properties are not easily computed without a preliminary
optimization of preferred conformations and good initial estimates. The accurate prediction of
the solubility of complex multifunctional compounds at the moment still remains an elusive
target.
• Oral activity prospects are improved through increased potency, but improvements in solubility or
permeability can also achieve the same goal. Despite increasingly sophisticated formulation
approaches, deficiencies in physico-chemical properties may represent the difference between
failure and the development of a successful oral drug product.
49

50. 1. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate
solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews
2012;64, Supplement:4-17.
2. Williams HD, Trevaskis NL, Charman SA, et al. Strategies to address low drug solubility in discovery and
development. Pharmacological reviews 2013;65(1):315-499.
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