Speaker Substitution for this Webinar!

Abu Serajuddin, Ph.D., joined St. John's University, Queens, NY, as Professor of
Industrial Pharmacy in September 2008 after a career of three decades in the
pharmaceutical industry with increasing scientific and managerial responsibilities at
Sanofi-Aventis (through mergers), Bristol-Myers Squibb and Novartis. In his latest
positions in the industry, Dr. Serajuddin served as Executive Director and the US Head
of Drug Product Development (1999-2003) and the Global Head of Science and
Technology (2003-2008) for Novartis Pharmaceuticals Corp. At St. John's, he is building
Abu Serajuddin,
Serajuddin, Ph.D. active research programs and centers of excellence in drug delivery sciences and
Professor, Industrial Pharmacy pharmaceutical processing technologies. He contributed extensively to basic
St. John’s University, Queens, pharmaceutics and drug delivery systems. He authored over 70 research papers and

New York book chapters and made over 60 invited presentations in major scientific conferences
(US, France and China). He is a co-inventor in 14 patents, the majority of the patents
being on drug delivery technology platforms. Among his professional recognitions, he
attained Fellow status in American Association of Pharmaceutical Scientists (AAPS),
American Pharmacists Association (APhA), International Union of Pure and Applied
Chemistry (IUPAC), and American Association of Indian Pharmaceutical Scientists
(AAiPS). He serves in the Editorial Advisory Board of Journal of Pharmaceutical
Sciences. He chaired AAPS Pharmaceutics and Drug Delivery Section (2001) and AAPS
Preformulation Focus Group (1994-1996). Currently, he is Chair of the AAPS Fellows
Committee for the FDD Section. A graduate in pharmacy from Dhaka University,
Bangladesh, Serajuddin received his Ph.D. in Industrial Pharmacy from St. John's
University, New York, M.S. in Pharmaceutics from Columbia University, New York, and
Advanced Training in Industrial Pharmacy from the University of Pisa, Italy.

Speaker Substitution for this Webinar!

Dr. Serajuddin published extensively on various aspects of pharmaceutical

salts, including the following review articles and book chapters:

A. T. M. Serajuddin, Salt Formation to Improve Solubility, Adv. Drug Del.

Rev. 59:603-616 (2007)

Abu Serajuddin,
Serajuddin, Ph.D. M. Pudipeddi, A. T. M. Serajuddin, D. J. W. Grant and P. H. Stahl. Solubility
Professor, Industrial Pharmacy and Dissolution of Weak Acids, Bases and Salts. In IUPAC Handbook of
St. John’s University, Queens, Pharmaceutical Salts: Properties, Selection and Use, P.H. Stahl & C. G.
New York Wermuth (eds.), Verlag Helvetica Chimica Acta, Zurich, Switzerland, 2002,

Chapter 2, pp. 19-39.

A. T. M. Serajuddin and M. Pudipeddi. Salt Selection Strategies. In IUPAC

Handbook of Pharmaceutical Salts: Properties, Selection and Use, P.H.
Stahl & C. G. Wermuth (eds.), Verlag Helvetica Chimica Acta, Zurich,
Switzerland, 2002, Chapter 6, pp. 135-160.

1
 Pharmaceutical Salts

Abu Serajuddin, Ph.D.

Professor, Industrial Pharmacy
St. John’s University, Queens, New York

Agenda
Follow me …
… on a trip through the world of
pharmaceutical salts

Let‘s visit different sites to address:

How do pharmaceutical salts influence drug
solubility?

What impact do they have on drug dissolution?

Can the salt for a particular compound be formed?

How are the salts identified and selected?

Case studies

2
 Drug Solubility

Importance of Aqueous Solubility

BCS Class Solubility Permeability

I high high
the rate-limiting step for drug absorption is gastric emptying
II low high
drug dissolution may be the rate-limiting step for drug absorption
III high low
drug permeability may be the rate-limiting step for drug absorption

IV low low
both solubility and permeability are factors; present major problem for oral delivery

According to BCS…
A drug is soluble if dose dissolves in 250
mL of buffer at pH 1 to 8
Ref: Amidon et al. Pharm. Res. 12 (3) 1995, 413-420, & The FDA Guidance to Industry: Dissolution
6 testing of immediate release solid oral dosage forms, 1997

3
 Drug Dissolution

Diffusion Layer Model

DA
J = dM = (Cs - C ) Cs
Cs
dt h
where
J = dM/dt = dissolution rate Bulk Liquid
D = diffusion coefficient Solid A Phase
(Dissolution Medium)
A = effective surface area
h = diffusion layer thickness
Stagnant
Cs = solubility of the solute Diffusion
C = concentration in the bulk Layer C
phase at a particular time
h
7

What is a Poorly Water-Soluble Drug?

According to the USP…

– Very slightly soluble:
0.1 mg/mL to 1 mg/mL
– Insoluble or practically insoluble:
insoluble:
< 0.1 mg/mL (100 µg/mL)
– There is no limit how low a solubility can be.

Most poorly water-

water-soluble compounds that prompted
dissolution and bioavailability-
bioavailability-bioequivalence guidelines in
1970s and 1980s had solubility in the range of 15 to 100
µg/mL..
µg/mL

Solubility of <10 µg/mL was practically unheard of; lovastatin
and simvastatin with solubility ~7 µg/mL were developed in
8 late 1980s.

4
 Present Status of NCE Solubility
Two-thirds (?):
Two- Very slightly
Insoluble or soluble or
50 Practically soluble
Insoluble
Percent 40

30

20
New
Generation
10

0
<10µg/mL
<10µg/mL 10-
10-100
100µg/mL
µg/mL >100µg/mL
>100µg/mL
Solubility

Solubility < 1 µg/mL (0.001 mg/mL) is common

9 Source: Personal experience, literature data and anecdotal information

Impact of Low Solubility on Drug Product

Development
Question:
How much water will it require to
dissolve a 500-
500-mg dose with the
Dose
following drug solubility?
Answer: Number:
100 µg/mL (0.1 mg/mL ) 5L 20
10 µg/mL (0.01
(0.01 mg/mL) 50 L 200
1 µg/mL (0.001 mg/mL) 500 L 2000
0.1 µg/mL (0.0001 mg/mL) 5000 L 20000
DN<20: Challenging but
may be doable
DN>20: Extremely
challenging
10

5
 Salt Solubility and Dissolution

Salt Solubility

Monobasic
Compound
Solubility Solubility of salt pHmax

Solubility of free base

Solid Phase: Salt Solid Phase:

pH Base
Ref: Serajuddin, Salt Formation to Improve Solubility, Adv. Drug Del. Rev. 59 (2007):603-
(2007):603-616
12Serajuddin & Pudipeddi, in Handbook of Pharmaceutical Salts, IUPAC, 2002

6
Effect of Salt Formation on Drug Solubility

pH-Solubility Profile of Haloperidol Mesylate,

Hydrochloride and Phosphate

100000 30 mg/mL
Line: fitted by equation
Log Solubility (µg/mL) Mesylate

HCl

1000
Phosphate

10

2.5 µg/mL
Mesylate > HCl > Phosphate
0.1
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
pH

Ref: S. Li, S.M. Wong, S. Sethia, H. Almoazen, Y.M. Joshi and A.T.M. Serajuddin.
Investigation of Solubility and Dissolution of a Free Base and Two Different Salt
13 Forms as a Function of pH. Pharm. Res. 22:628-635 (2005)

Dissolution Profiles of a Free Base

Intrinsic dissolution of haloperidol base

35
Cumulative amount released

pH 2.05
30
25
20
(mg)

15
10
pH 3.08
5 pH 1.1
pH 5.0
0
0 15 30 45 60 75 90 105 120
Time (min)
Solubility is practically zero under intestinal pH conditions (5 and higher)
Ref: S. Li, S.M. Wong, S. Sethia, H. Almoazen, Y.M. Joshi and A.T.M. Serajuddin. Investigation of Solubility and
14 Dissolution of a Free Base and Two Different Salt Forms as a Function of pH. Pharm. Res. 22:628-635 (2005)

7
 Dissolution Rates of Salt Forms of a
Basic Compound
Intrinsic dissolution of haloperidol hydrochloride Intrinsic dissolution of haloperidol mesylate

40 300
pH 3.08
35 pH 3.05
pH 5.02 250
pH 5.01

Cumulative amount released (mg)

Cumulative amount released (mg)

30
pH 7.0
200
25
pH 7.0
20 150
pH 2.02
15 pH 2.08
100

10

50
5
pH 1.1 pH 1.65
0 0 pH 1.08
0 15 30 45 60 75 90 105 120 0 15 30 45 60 75 90 105 120
Time (min) Time (min)

Ref: S. Li, S.M. Wong, S. Sethia, H. Almoazen, Y.M. Joshi and A.T.M. Serajuddin. Investigation of Solubility and
15 Dissolution of a Free Base and Two Different Salt Forms as a Function of pH. Pharm. Res. 22:628-635 (2005)

How Does Salt Formation Increase

Dissolution Rate?

Diffusion Layer Model

J = dM = DA (Cs - C )
dt h
Cs, h=0 >> Cs, bulk medium
…. by changing
microenvironmental
pH and solubility Bulk Liquid
Solid Phase
(salt) (Dissolution Medium)

•Saturate
•Supersaturate, Stagnant
Diffusion
and/or Layer
•Fine precipitate C

h
16

8
 Effect of Solid Surface pH on Dissolution
Solid Surface
Diffusion Layer Bulk Medium
7
Hydrochloride Salt:
Effects of Dissolution 6
Media on Cs,h=o
5

pH
3

h=o h=h
Ref: Serajuddin & Jarowski, J. Pharm. Sci., 74, 148-
148-154,1985.

Limitation of Salt Formation for the New

Generation of Poorly Water-soluble Drugs

Diffusion Layer Model

When the intrinsic
solubility is very low, the
precipitated free base X
Cs, h=0 >> Cs, bulk medium
coats the dissolving
Precipitated Free Base

surface,, preventing
surface
further dissolution of salt.
Bulk Liquid
Please note: Precipitation
at the surface, not in the
Solid
(salt)
X Phase
(Dissolution Medium)

bulk medium. No increase

Stagnant
in surface area. Diffusion
Layer

h
18

9
Differentiation of Dissolution Rates of
Free Acid vs. Salt
pH 2.0 pH 6.8

100 100
Fraction of Compound 4 Dissolved

Percent Com pound 4 Dissolved (%)

80 80

60 60

40 40
Salt
20 Salt
20 Free acid
Free acid

0 0
0 10 20 30 40 0 20 40 60 80
Time (m in) Time (m in)

Dose = 200 mg; pKa = 4.3

Traditional dissolution test could not distinguish
between weak acid and its potassium salt

19

Salt vs. Free Acid: in vivo result

Human Cp-t profile of free acid and its salt

Conc (ng/mL)

6000

5000

4000
Acid
3000
K-Salt
2000

1000

0
0 2 4 6 8 10 12 14 16 18 20 22 24

Time (h)

20

10
Alternative Dissolution Method Needed to
Distinguish between Free Acid and Salt

100

90

80

70
% Dissolved

60

50
pH 6.8
40

30 pH 5.5 Salt

20 Free acid

10 pH 2.0
0
0 20 40 60 80
Time (min)

Gradient dissolution could distinguish between the

two forms and establish IV-IVR.

21

Differentiation of Dissolution Rates of Free

Base vs. its Salt Forms
pH 2.0 pH 4.0
100
Cumulative Percent Released

100
Cumulative Percent Released

80 80
di HCl
60
60 free base
suspension 40
tartrate
40
20

0
20
0 10 20 30 40 50 60

Time (minutes)
0
0 10 20 30 40 50 60

Time (minutes)

Amount = 100 mg/capsule

Ref: Li, Royce & Serajuddin. Biopharmaceutics Application in Drug

Development. Krishna & Yu, ed. Springer, 2008.
22

11
PK Profiles of Free Base vs. its Salt Forms
in Dogs

Plasma Concentration 6000 Free base susp. (10 mg/kg)

5000 Tartrate in cap. (10 mg/kg)
DiHCl in cap. (10 mg/kg)
(ng/mL)

4000
3000
2000
1000
0
0 20 40 60
Time (h)

Ref: Li, Royce & Serajuddin. Biopharmaceutics Application in Drug Development.

23 Krishna & Yu, ed. Springer, 2008.

Salt Selection

12
Selection of Chemical Form
First Important Question
– Is the preparation of an ‘acceptable’ salt form
feasible?
Possibly the Next Question and a Few Answers
– What are the attributes of an ‘acceptable’ salt
from a chemical consideration?
• Has desired aqueous solubility (and dissolution
rate)
• Does not dissociate into free base/acid form as
bulk drug substance and in dosage forms
• Chemically stable

Selection of Chemical Form

Present Status
– No predictive method to determine whether a
particular acid/base would form salts with
certain counter-
counter-ions
Some General Approaches
– pKa of conjugate acid smaller than the pKa of
conjugate base to ensure sufficient proton
transfer from acidic to basic species
– For a basic drug, pKa of acid used should be
at least 2 pH units lower than pKa of drug

13
 pH-Solubility Considerations in Salt Selection

Monobasic ST = [BH+]s +[B]

= [BH+]s {1 + Ka/[H3O+]}
Compound
pHmax

Solubility
ST = [BH+]+[B]s
= [B]s {1 + [H3O+]/ Ka}

Solid Phase: Salt Solid Phase: Base

pH
Ref: Kramer & Flynn, J. Pharm. Sci.,
Sci., 61, 1896-
1896-1904,1972.

Typical pH-Solubility Profiles: Haloperidol

100000
Mesylate
ο Hydorochloride
∆ Phosphate
Solubility, µg/mL

1000

10

0.1
0 2 4 6 8 10 12 14

pH

14
 Feasibility of Salt Formation - Compound A

How can pH-solubility principle be used for

Compound A? O
O
N
O O

O
O N N N
H H H O
OH OH

pKa = 8.1
So = 0.06 mg/mL

pH-Solubility Profile of Compound A

20
pHmax
16

Solubility 12
mg/mL
8
HCl solution used

4 to adjust pH

0
1 3 5 7 9 11
pH

15
Feasibility of Salt Formation - Compound A

 pHmax ~ 5.5
 pH can be lowered below 5.5 with strong as
well as relatively weak acids
 Salt formation with most common counter-
ions might be feasible
 Acetate, fumarate, succinate
and hydrochloride salts had acceptable
crystallinity
 A relatively simple case!

Another Example: Another Solubility Profile

How will a compound with pKa = 5.7 and So = 3.4 µg/mL form salts?

 Over 60 attempts with numerous counter-ions made.

 Only HCl and mesylate salts formed. HCl salt had low aqueous solubility.
Could these not be predicted from pH-Solubility profile?

1500.00
s olubility (m c g/m l)

pHmax = 3.2 SRA701

1000.00

500.00

0.00
0.0 2.0 4.0 6.0 8.0 10.0 12.0
pH

16
 Another Example - Compound B

OH
O
N

pKa = 3.6; So = 0.002 mg/mL

 Will it form a salt?
 Only with relatively strong acids?

Lets first look at the pH-

pH-solubility
relationship

pH
pH--Solubility Profile of Compound B

1.0
0.08
pHmax = 1.0
0.06
0.8
Solubility
mg/mL 0.04
Solubility 0.6
0.02
mg/mL
0.4 0
2 3 4 5

pH
6
0.2

0
0 1 2 3 4 5 6
Ref: Serajuddin et al., J. Pharm. Sci.,
Sci., 75, 492-
492-496,1986. pH

17
Feasibility of Salt Formation: Compound B

What did we learn from pH-solubility profile?

 pHmax = 1.0; pH in aqueous media must be
lowered below 1 to form salt
 Salt formation with strong acids could possibly be
feasible
 Indeed, hydrochloride and sulfate salts could be
prepared with difficulty; hygroscopic, chemically
unstable, easily converted to free base, dissolved
poorly
 Free base was selected for development

Another Example: Compound C

O
F F
N F F
H F
 Was compound B also a F

relatively simple case?

N O
 What about Compound C
N
N
with a higher pKa value? H

pKa ~ 5.5-
5.5-6.0
Solubility <0.0001 mg/mL
at pH>6

18
pH-Solubility Profile of Compound C

0.12  No acceptable salt could be

0.1 synthesized despite a higher pKa

0.08 value
Solubility
 Could it be predicted from
0.06
mg/mL the pH-solubility profile?
0.04
0.02
0
0 1 2 3 4 5 6 7
pH

Prediction of Salt Formation

Are Experimental pH-
pH-Solubility Profiles
Essential to Determine the Feasibility of
Salt Formation?
– Not necessarily.
– Can be theoretically predicted from pKa and
intrinsic solubility (So)
– Solubility of salt form, however, remains
unknown.
– pHmax may be approximated for different
arbitrarily selected solubility values for salts

19
 Theoretical Modeling of pH-Solubility
Profiles

Effect of Intrinsic Solubility (So) on pHmax of a Base (pK

(pKa = 8.0)
50
ST = [BH+]+[B]s
40 = [B]s {1 + [H3O+]/ Ka}

30

Solubility So = 0.0001 0.001 0.01 0.1 1 10 mg/mL

20
mg/mL
10

0
0 2 4 6 8 10
pH

Effects of pKa, So and Ksp

20
 General pH-Solubility Considerations

Monoprotic ST = [A-]S + [AH]

= [A-]S {1 +
Acid pHmax
[H3O+]/Ka}

Solubility ST = [AH]s + [A-]

= [AH]s {(1 +
Ka/[H3O+]}

Solid Phase: Acid Solid Phase: Salt

pH
Ref: Chowhan
Chowhan,, J. Pharm. Sci.,
Sci., 67, 1257-
1257-1260,1978.

Feasibility of Salt Formation for

Acidic Drugs
pH Solubility Profile of Phenytoin at 37°
37°C
140
120 H
100
6 C6H5 N O
4
0 C6H5
2
0
Solubility 0
1
NH
O
0
6
mg/mL 4
2 pKa = 8.4
1 So = 0.04 mg/mL
0.6 Free Acid
0.4
0.2
0.1 Sodium Salt
0.06
0.04
0.02
0 2 4 6 8 10 12 14
pH
Indicates salt formation with only strong counter-
counter-ions
Ref: Serajuddin & Jarowski., J. Pharm. Sci., 82, 306-
306-310,1993.

21
 pH-Solubility Relationship of a Dibasic
Compound
CH3 H CH3 H
N N
N N
O S O
O S O N
N OCH3
OCH3
N
N
pKa1 = 8.0
HN N
HN N + H

H
CH3 H
N N+ pKa2 = 3.6
So = 0.006 mg/mL O S O
N
OCH3
N

HN N
+ H
Serajuddin & Pudipeddi, in Handbook of Pharmaceutical Salts, IUPAC, 2002

pH-Solubility Relationship of Compound D

Acids Used to Adjust pH in pH-

pH-Solubility Determination

Acid pKa
HCl (-) 6.1
Methanesulfonic acid (-) 1.2
Acetic acid 4.8
Lactic acid 3.9
Tartaric acid 3.0, 4.4
Succinic acid 4.2, 5.6

22
 Results for Compound D

Solubilities of Salts Formed (mg/mL at 25°

25°C)

Acids Used Mono--salt

Mono Di
Di--salt

HCl 3.4 9.0

Methanesulfonic acid 16.3 Di-
Di-salt not formed

Acetic Acid 16.5 “

Lactic Acid 15.2 “
Succinic Acid 16.1 “
Tartaric Acid 14.7 “

pH-Solubility Profile of Compound D

Counterion: 35 0. 8

Hydrochloric Acid 30 pHmax2 0. 6

Solubility

0.4
25
0.2
Solubility 20 pHmax1 0
5 6 7 8 9 10
mg/mL 15 pH

10 pKa = -6.1
HCl
5

0
1 3 5 7 9 11
pH

23
 pH-Solubility Profile of Compound D

Counterion: 60
Mesylic Acid H3SO3H
50
(pKa = -1.2)
40
Solubility
30
mg/mL
20

10

0
1 3 5 7 9 11
pH

pH-Solubility Profile of Compound D

Counterion: 80

Tartaric Acid pKa = 3.0, 4.4

60 COOH

Solubility CHOH
40
mg/mL CHOH

COOH
20

0
1 3 5 7 9 11
pH

24
 What Could We Learn from
pH-Solubility Profiles of Compound D?
 pHmax ~ 5 and ~ 2

 While all acids used could lower pH below 5

(pHmax1), only HCl could lower pH below 2 (pHmax2)
 HCl would form either mono- or di-salt

 All other acids used would form mono-salt

 Attempts to synthesize di-salt forms and attempts to

look for them in samples produced can thus be
reduced/avoided
 For Compound D, no di-salt other than
dihydrochloride could be produced

Practical Considerations: Effects of Non-

Non-
Aqueous or Mixed Solvents

 Increase free acid/base solubility  Positive impact on pHmax

 Decrease salt solubility  Salt formation is favored

 Decreases pKa of base  Negative impact on pHmax

 Increases pKa of an acid  Salt formation is not favored

Examples:
 pKa of an acid is raised by ~1 and that of a base is lowered by
~0.5 in 60% methanol
 pKa values of benzoic acid are 4.2, 12.3, 11.0 and 20.7 in water,
DMF, DMSO and AN, respectively

25
Practical Considerations: What Happens When
Multiple pKa Values are Not Well-
Well-Separated ?

For example,
what types of salt(s) will a basic drug with pKa values
of 8, 6 and 4 and So = 0.002 mg/mL form?
 pHmax may not be well-separated
 Preparation of salts (mono-, di-, or tri-) might be difficult
 Nucleation of mono- and di-forms may be hindered due to
lack of supersaturation with a particular salt form (This is the
result of multiple ionization)
 Crash precipitation may lead to amorphous forms and non-
stoichiometry

Salt Form Selection: A Multi-Tier Approach

Tier 1  Crystallinity (visual, microscopy)

 Crystallization from different solvents
 Aqueous solubility/microscopic examination of suspended solid

Tier 2  Evaluation of crystalline form (powder x-ray, hot stage microscopy)

 Thermal properties (DSC, TG)
 Hygroscopicity
Tier 3  Humidity/temperature-dependent changes in crystal form
(powder x-ray, DSC, TG, VT-XRD, etc.)

Tier 4 Bioavailability screening (optional)


Stress stability

Scale up considerations

Final Form Ref: Morris et al. Int. J. Pharm. 105:209-217 (1994)

26
Salt Selection: A Systematic
Approach

Conclusions
– A systemic approach for identification
of optimal chemical and physical forms for
development is presented
– This minimizes guess work and reduces trial
and error
– By simple pH-
pH-solubility considerations, number
of attempts in salt preparation can be greatly
reduced
– By this simple approach, drug development can
be accelerated through savings of time and
resources

27