lesson 3 preformulation i solubility profile (solubility
TRANSCRIPT
SWAYAM MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB
Garhwal University (A Central University) Srinagar (Garhwal) Uttarakhand, India
Lesson_3
Preformulation I
Solubility Profile (solubility, pH and pKa)
-Dr Ajay Semalty
Department of Pharmaceutical Sciences,
H.N.B Garhwal University (A Central University)
Srinagar Garhwal-246174
Learning outcomes
After learning this module you will be able to understand
• Concept of Solubility
• Importance of Solubility in Preformulation
• Concept of pH and pKa
• Interrelation of solubility, pH and pKa
• Methods of improving solubility
• Characterization of solubility
Lesson Plan
• Concept of solubility
• Methods of improving solubility
• Characterization of solubility
• pH, pKa, concept and importance
• Determining/Characterization of pKa
• Importance, characterization and inter relation with respect to
preformulation
Dear learners, after going through the crystallinity and polymorphism let’s
learn some other physical properties like solubility, pH, pKa and partition
coefficient with respect to preformulation.
Module 3: Preformulation I Solubility Profile (solubility, pH and pKa) 2
SWAYAM MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB
Garhwal University (A Central University) Srinagar (Garhwal) Uttarakhand, India
Do you remember that in the last module we discussed about greater
solubility of amorphous form or of the API in small in particle size. Can you
guess………..
To enter in the systemic circulation, the API is needed to go into the solution
(GIT fluid for oral route or in the solvent of formulation in case of injectable).
And then it has to pass across the biological membranes to enter in to the
systemic circulation (vascular system). For passing across, it has to be
partitioned into the non aqueous or lipid phase present in lipid bilayer
biomembranes. This partitioning is represented by the physical property
partition coefficient or more precisely it is called permeability of the API.
Let’s move to solubility first
SOLUTE
SOLVENT SOLUTION
“The extent of solute dissolved in a unit amount of solvent in certain
conditions of temperature, and pH.”
- Solubility
Have you experienced dissolving sugar in normal water, chilled water and
boiling water. With the increase in temperature you need more amount of
solute to prepare a clear solution. So solubility is dependent on temperature. It
also depends on pH.
In preformulation, at the early stage of drug formulation development you
may have only a very small quantity (about 50 mg) that to, not much in
Module 3: Preformulation I Solubility Profile (solubility, pH and pKa) 3
SWAYAM MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB
Garhwal University (A Central University) Srinagar (Garhwal) Uttarakhand, India
pure state. So, minimum requirement at that time is to determine solubility
and pKa.
Solubility is required for dosage form development for oral route, injectibles
and other formulations.
The pKa determination allows using a particular pH to maintain solubility and
to choose the suitable salt form for improved bioavailability, stability and
powder properties.
Minimum expected solubility
For formulation perspective, the drugs which have the water solubility less
than the 10 mg/ml (over the pH range of 1 to 7 at 37 ºC) show the potential
bioavailability problems (Kaplan, 1972). Solubility and dissolution are well
connected. Dissolution is the solubility with function of time in the suitable
solvent (rate and extent of solute going in to the solution).
The lower limit (below this absorption and bioavailability problem occurs) of
Intrinsic dissolution rate is 1mg/cm2.min
While lower limit of dissolution rate is 0.1 mg/cm2.min
So, in light of the above practically the lower limit of solubility is 1mg/ml.
If solubility < 1 mg/ml, then solubility improvement by use of suitable salt
form is must. Rather it becomes necessary in the range of 1- 10 mg/ml.
If salt form is not possible by salt formation [like in case of neutral molecules
– glycosides, steroids, alcohols or for API which have pKa < 3 (for a base) or
> 10 (for an acid)] then liquid filling in soft or hard gelatin capsules remains
the option.
Module 3: Preformulation I Solubility Profile (solubility, pH and pKa) 4
SWAYAM MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB
Garhwal University (A Central University) Srinagar (Garhwal) Uttarakhand, India
Determining nature of drug and salt selection
Solubility in
acid compared
to aq. Solubility
Solubility in
base compared
to aq. Solubility
Nature of drug Need of form
- Weak Base pKa can be
measured; salt
should be formed
- Weak Acid pKa can be
measured; salt
should be formed
Amphoteric or
zwitterion
Two pKa,
- - Neutral Molecule No measurable
pKa; solubility
manipulation by
solvent or
complexation
Salt formation
For the salt formation strong acids or bases are avoided because they may be
freely soluble but are too hygroscopic to be used in tablet or capsules. So it’s
better to prepare the salts of weak acid and bases. Salt forms are most
commonly used for improving the solubility and dissolution. Sometime the
less soluble salts are intentionally used for specific reasons masking the taste
(chloramphenicol palmitate); protecting the parent drug from excessive
degradation in the gut, e.g. erythromycin Propionate; sustained release
(propranolol laurate) etc.
“In the case of propranolol, a drug subject to first-pass metabolism, the
hydrophobic laurate counterion was selected in order to reduce the aqueous
solubility and dissolution rate, thereby sustaining its release. When tested in
dogs, the laurate salt resulted in improved bioavailability compared to the
hydrochloride salt in immediate- and sustained-release formulations.”
Module 3: Preformulation I Solubility Profile (solubility, pH and pKa) 5
SWAYAM MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB
Garhwal University (A Central University) Srinagar (Garhwal) Uttarakhand, India
So again stability, safety and efficacy may be the selection criterion of
suitable salt form. However, the efficacy doesn’t vary salt to salt of a parent
drug until dosage is increased very highly. Biopharmaceutical properties like
dissolution rate, onset of action, duration of action, concentration at particular
site, Cmax, Tmax and stability vary with the salt selection.
In Pharma industry the hydrochloride, sulphate, maleate, potassium, sodium
and calcium salts are used 43.0, 7.5, 3.0, 10.8, 62.0 and 12.9 %, respectively.
We discussed in previous module that by selecting a suitable crystal form/
solvate/hydrate, the solubility can be modulated.
Other methods of improving or modulating solubility are
Use of co-solvent
Hydrotrophy method
By addition of polar group
Use of solid solution
Solid dispersion
Eutectic mixture
Microni-zation
Use of surfactants
Alternation of pH of solvent
Use of suitable crystal form or metastable polymorphs
Solvates formation
Selective absorption on insoluble carrier
Cyclodextrin complexation
Phospholipid complexation
Module 3: Preformulation I Solubility Profile (solubility, pH and pKa) 6
SWAYAM MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB
Garhwal University (A Central University) Srinagar (Garhwal) Uttarakhand, India
Methods of Improving/modulating solubility
Methods Mechanism involved Methodology Examples
Use of suitable
salt Increase in dissolution
Salt formation with
weak acid or base
Chlordiazepox
ide maleate,
diclofenac
sodium
Use of co-
solvent
Increase in solubility of drug Addition of co-solvent
ethanol, propylene,
glycol, glycerin
Analgesic
syrups of
paracetamol
Hydrotrophy
method
Addition of large amounts of a
second solute results in an
increase in the aqueous
solubility of another solute
Adding hydrotropic
agents like urea,
nicotinamide etc.
Paracetamol
By addition of
polar group
Increasing water solubility by
increasing hydrogen bonding
and interaction with water
Addition of polar group
in the structure of drug
(carboxylic acid and
amine)
--
Use of solid
solution
Improving solubility by
preparing sol-gel form of the
drug
Fusion, melting Succinic acid
Solid dispersion Decreasing the drug’s particle
size changes the
microenvironment of the drug
particle which increases the
dissolution rate and absorption
Prepared by fusion,
solvent evaporation,
Paracetamol-
urea
Eutectic
mixture
When exposed to water the
soluble carrier dissolves leaving
the drug in micro crystalline
state which solubilize rapidly
Fusion
Paracetamol-
camphor
Microni-zation Increasing the effective surface
area of drug by decreasing
particle size
By spray drying and by
use of fluid energy mill
Griesiofulvin
and several
steroidal and
sulpha drugs
Use of
surfactants
By promoting wetting and
penetration of dissolution fluid
into the drug
Addition of suitable
surfactants
(polysorbate)
Spironolacton
e is a drug
whose
bioavailability
is increased
by this
method
Alternation of
pH of solvent
Changing the pH of drug in
solution
Salt formation, addition
of buffer
Buffered
tablets of
aspirin
Use of
metastable
polymorphs
Metastable forms show better
solubility than stable form
Converting the stable
form to metastable form
Using B form
of chlorom-
phenicol than
A and C
forms
Solvates Powder of submicron size Freeze drying of solute Benzene
Module 3: Preformulation I Solubility Profile (solubility, pH and pKa) 7
SWAYAM MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB
Garhwal University (A Central University) Srinagar (Garhwal) Uttarakhand, India
formation having increased surface area
show the improved solubility
with organic solvent solvate
Selective
absorption on
insoluble
carrier
Weak physical interaction
between adsorbate and
adsorbant through hydration
and swelling of clay in aqueous
media improves solubility
Use of highly active
adsorbant, clay like
bentonite
Indomethacin,
Prednisone
Cyclodextrin
complexation
Inclusion of hydrophobic
groups of drug in the core of
cyclodextrin cavity and thereby
improving solubility
Formation of drug
Complex with
cyclodextrin (α, β, γ) or
its derivatives
Meloxicam,
phenytoin,
Phospholipid
complexation
Drug-Lipid complexes improve
amorphous nature of drug in the
complexes and being
amphiphilic in nature the
complex show improved
solubility and dissolution
The phospholipid
complexes of drug
without the presence of
covalent bond are
formed.
aceclofenac,
aspirin,
curcumin,
silybin etc.
*Adapted from Semalty et al. Essentials of Pharmaceutical Technology, II edn,
Pharma med Press, Hyderabad, 2018.
Intrinsic solubility (So)
Solubility of a pure weak acid in acid and pure weak basic in alkali is called
Intrinsic solubility (So). It is the fundamental solubility when completely
unionized.
The solubility should be measured at two temperatures- 4 oC (for ensuring
physical stability and extending short term storage and chemical stability) and
37 oC (for supporting biopharmaceutical properties at body temperature).
The solubility of the pure form is determined by phase solubility diagram.
In Phase Solubility study, the amount of drug to the amount of dissolving
solvent is varied and solubility noted and recorded as in this graph.
Module 3: Preformulation I Solubility Profile (solubility, pH and pKa) 8
SWAYAM MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB
Garhwal University (A Central University) Srinagar (Garhwal) Uttarakhand, India
Impurity either increases or decreases the solubility. Impure form gives a non
horizontal curve which intersects the y axis at a point which is actually the
intrinsic solubility.
By this way, the solubility of the pure form of API can be determined from
the impure form available at the time of preformulation stage.
Solubility definition and classification (as per IP and USP)
Description Parts of solvent required
for one part of solute
Very soluble <1
Freely soluble 1-10
Soluble 10-30
Sparingly soluble 30-100
Slightly soluble 100-1000
Very slightly soluble 1000-10,000
Insoluble >10,000
Measuring solubility:
Add excess amount of solute in a certain amount of solvent at specific
temperature and pH. Allow the solution to be agitated/stirred overnight to
Module 3: Preformulation I Solubility Profile (solubility, pH and pKa) 9
SWAYAM MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB
Garhwal University (A Central University) Srinagar (Garhwal) Uttarakhand, India
establish equilibrium. After the overnight stirring, centrifuge or filter the
sample and analyzed spectrophotometrically or by some other means for
knowing the concentration. This will be the solubility at particular
temperature and pH.
pH
pH = − Log [H+]
pH scales from 1 to 14
acid pH < 7
neutral = 7
alkali/basic= >7
Importance of pH in preformulation
1. Injections should be in range of pH 3-9 to prevent tissue damage and pain
at injection site.
2. Oral syrups can not be formulated too acidic for palatability reasons.
3. More alkali may attack the glass container.
4. If drug is susceptible to degradation in acidic pH, then its delayed release
formulation is to be prepared.
5. The pH of formulation must not sensitize the site of application. e.g. pH for
buccal application should in the range of 6.6 to 6.8.
6. GIT shows a variety of pH [pH 6.6 (buccal), pH 1.2 (stomach), pH 6.8
duodenum, pH 7-8 (small intestine)] throughout its length from oral
cavity to colon. The dosage form should be stable at the pH of the
intended or target site of absorption.
Module 3: Preformulation I Solubility Profile (solubility, pH and pKa) 10
SWAYAM MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB
Garhwal University (A Central University) Srinagar (Garhwal) Uttarakhand, India
Ionization constant (pKa)
Strong acids, e.g., HCl, are ionized at all pH values, whereas the ionization of
weak acids is dependent on pH.
Why are we more concerned about weak acid or base? Because, most of the
drugs are either weak acid or base or its salt.
It is very important to know the extent to which the molecule is ionized at a
certain pH, since properties such as solubility, stability, drug absorption and
activity are affected by this parameter. The Ionization constant (pKa) provides
this information.
The relationship of pH and pKa
HA H+ + A
−
NaOH
Na+
+ OH
−
How strong an acid is determined by acid dissociation constant.
Smaller the acid/base dissociation constant weaker the acid or base.
a= [H+] [A
−]/ [HA] ….. for a weak acid
Bigger the Ka stronger the acid
Kb = [Na+] [OH
−]/ [NaOH] …….. for a weak base
Henderson Hasselbalch equation defines the ratio of the two species
(unionzed and ionized)
pKa = - log Ka and; pH= -Log [H+]
pH = pKa + Log [A−]/ [HA] Eq.1
or
Module 3: Preformulation I Solubility Profile (solubility, pH and pKa) 11
SWAYAM MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB
Garhwal University (A Central University) Srinagar (Garhwal) Uttarakhand, India
pH = pKa + Log [Base]/ [Acid] Eq.2
for weak base
pOH = pKb + Log [BH+]/ [B] Eq.3
or
pOH = pKb + Log [Acid]/ [Base] Eq.4
[It should also be noted that, usually, pKa values are preferred for bases instead of
pKb values (pKw = pKa + pKb).]
pH = pKa + Log [B]/ [BH+] Eq. 5 (for weak bases)
So the HH Equation can be used
1. To determine pKa with the change in solubility
2. To predict solubility at a pH (If Co and pKa are known)
3. To select suitable salt and its properties like pH and solubility.
In the equation 1 if when an acid is exactly half ionized [A−] = [HA] and
hence pKa = pH
So, the “pKa value is the pH at which acidic or basic groups attached to
molecules exist as 50% ionized and 50% nonionized in aqueous solution.”
“For acids, a pH below the pKa enhances absorption, while for bases; a pH
above the pKa enhances absorption.”
Relating pH, pKa and solubility
The relationship between pH and the solubility and pKa value of an acidic
drug is given by modified Henderson Hasselbalch equation.
pH= pKa + Log (S − Su)/ Su ….. For weak acids
Module 3: Preformulation I Solubility Profile (solubility, pH and pKa) 12
SWAYAM MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB
Garhwal University (A Central University) Srinagar (Garhwal) Uttarakhand, India
Where S = Overall solubility
Su = Solubility of unionzed form (intrinsic solubility)
(S= Su + Si)
(The eq. provide the minimum pH that must be maintained to avoid
precipitation of weak acids.)
In the same way..
pH= pKa + Log Su/ (S − Su) ….. For weak Bases
Determination of pKa
pKa value may be determined by
Potentiometric titration,
UV spectotroscopy
Solubility measurements
HPLC techniques
Capillary zone electrophoresis
Foaming activity
Importance of pKa
The pKa value provides valuable data
on the interaction of an ionizable drug with charged biological
membranes and receptor sites;
information on where the drug may be absorbed in the GIT; The pH
varies in GIT regions so the ionization and hence the absorption of
drugs varies throughout the GIT
Module 3: Preformulation I Solubility Profile (solubility, pH and pKa) 13
SWAYAM MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB
Garhwal University (A Central University) Srinagar (Garhwal) Uttarakhand, India
to know how much to alter the pH to drive a compound to its fully
ionized or nonionized form for analytical and other purposes, such as
formulation, solubility, and stability.
Take away Message
“GIT shows a variety of pH (pH 6.6 (buccal), pH 1.2 (stomach), pH 6.8
duodenum, pH 7-8 (small intestine) throughout its length from oral cavity to
colon. Depending on pKa, drug may be charged or uncharged in different
regions and its absorption and hence the BA may vary (pH partition
hypothesis: Un-ionized drug is absorbed through membranes; Charges species
don’t get through easily; Ionization of drug molecule depends on pH of the
site e.g. weakly acidic drugs are unionized at acidic pH of stomach and hence
absorbed from the gastric region). For acids, a pH below the pKa enhances
absorption, while for bases; a pH above the pKa enhances absorption.”
Further Readings
pH https://www.youtube.com/watch?v=LS67vS10O5Y
Handerson Hasselbalch equation
https://www.youtube.com/watch?v=LJmFbcaxDPE
Acid/Base Dissociation Constant
https://www.youtube.com/watch?v=7C_HsfB_6PQ&t=308s
Distribution Coefficient (Partition Coefficient)
https://www.youtube.com/watch?v=naUKY6y0Uu4
Niazi SK, Handbook of Preformulation, Informa health care, 2007.
Gibson M. (Ed), Pharmaceutical preformulation and formulation: a
practical guide from candidate drug selection to commercial dosage
form, II edn, Informa Healthcare, 60- 75.
Qiu Y, Chang Y and Zhang GZ (Exe. Eds), Developing solid oral
dosage forms: Pharmaceutical theory and practice, Elsevier, 2009, pp
25-35.
Module 3: Preformulation I Solubility Profile (solubility, pH and pKa) 14
SWAYAM MOOC: Industrial Pharmacy-I by Dr Ajay Semalty (Course Coordinator), HNB
Garhwal University (A Central University) Srinagar (Garhwal) Uttarakhand, India
References
Niazi SK, Handbook of Preformulation, Informa health care, 2007.
Gibson M. (Ed), Pharmaceutical preformulation and formulation: a
practical guide from candidate drug selection to commercial dosage
form, II edn, Informa Healthcare, 60- 75.
Qiu Y, Chang Y and Zhang GZ (Exe. Eds), Developing solid oral
dosage forms: Pharmaceutical theory and practice, Elsevier, 2009, pp
25-35.
Semalty et al. essential of Pharmaceutical Technology, Pharma Book
Syndicate, Hyderabad.
Aulton ME (Ed), Pharmaceutics, The science of dosage form design,
II edn, Churchill Livingston, London, 2006, pp- 113-122..