Lesson 3 Preformulation I Solubility Profile (solubility

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



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




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.




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.”




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




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




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.




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




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.




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




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




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




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.

https://www.youtube.com/watch?v=LS67vS10O5Y

https://www.youtube.com/watch?v=LJmFbcaxDPE

https://www.youtube.com/watch?v=7C_HsfB_6PQ&t=308s

https://www.youtube.com/watch?v=naUKY6y0Uu4




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..

Documents

Lesson 3 Preformulation I Solubility Profile (solubility