Preformulation

One of the aspects of Preformulation research in the
pharmaceutical industry is the sequence of studies whereby
one characterizes a new drug substance so as to learn about
its properties and tendencies. To the latter-stage
developmental scientist, preformulation represents the stage
where formulations are developed that will allow the profiled
drug candidate to deliver its desired function in a dosage form
that will be stable for the intended shelf life. The course of
development science being what it is, problems inevitably
crop up during the preformulation work, and each much be
addressed, studied, and eventually solved. In this
presentation, an outline of a program of preformulation will be
presented that fits within the modern scope of drug
development, and an emphasis will be placed on the
recognition of problems before they become sufficiently
insurmountable so as to derail the development of the drug
substance.

Free Acid, Free Base, or Salt?
• An early question to answer is whether a
drug substance should be used in its free
acid or free base form, or whether a salt
form should be used.
• Salts are most commonly used to modify
undesirable traits of a drug substance, most
typically the aqueous solubility or the
dissolution rate.
• The decision as to which form to develop is
usually answered using laboratory work, but
it does not need to be.

Preliminary-Preformulation (1)
• In the computational approach, one begins
with the structure of the free base or free
acid form of the drug candidate.
• Using a suitable predictive program, one
calculates:
– Ionization constant(s)
– pH dependence of solubility
for the drug substance.

Preliminary-Preformulation (2)
Hydrocinnamic acid
calc pK
A1
= 4.65
O
OH
pH
S
o
l
u
b
i
l
i
t
y
(
m
g
/
m
L
)
2
4
6
8
10
12
14
0
200
400
600
800
1000
1200
Preliminary-Preformulation (3)
Amphetamine
calc pK
A1
= 9.94
(calc pK
B1
= 4.06)
CH
3
NH
2
pH
S
o
l
u
b
i
l
i
t
y
(
m
g
/
m
L
)
2
4
6
8
10
12
14
0
200
400
600
800
1000
1200

Salt Prediction (1)
• It can be shown that for the reaction of an
acid and a base in water, the equilibrium
constant expression is:
HA + B ↔
A
–
+ BH
+
• So that:
K
A
K
B
[A
–
] [BH
+
]
———
= ——————
K
W
[HA] [B]
 H.G. Brittain, ―Strategy for the Prediction and Selection
of Drug Substance Salt Forms‖, Pharm. Tech. (2007)
31(10): 78-88

Salt Prediction (2)
• We can define the equilibrium constant for
formation of the salt as:
K
S
= K
A
K
B
/ K
W
• K
S
may also be calculated using:
log(K
S
) = pK
W
– (pK
A
+ pK
B
)
• The degree of salt formation can be
calculated knowing the value of K
S
:
if log(K
S
) = 2, salt = 90.91%
= 3, salt = 96.93%
= 4, salt = 99.01%
= 5, salt = 99.68%

Selection of the Counterion
• Having calculated the pK
A
for the drug substance,
and having decided whether or not to prepare an
acid-addition or base-addition, one then calculates
the minimal value of K
S
that will provide a salt form
that resists disproportionation.
• For pharmaceutical compounds, the counterion
must also be ―pharmaceutically acceptable‖, so
one needs to consult the standard references to
identify suitable acids or bases:
S.M. Berge, L.D. Bighley, and D.C. Monkhouse, J.
Pharm. Sci., 66, 1-19 (1977).
P.H. Stahl and C.G. Wermuth, Handbook of
Pharmaceutical Salts, Wiley-VCH (2002).

Isolation of Salts
• Once 3-5 potential salt forms are identified,
these are to be prepared:
1. Crystallization from various solvents
2. Thermal processing of solids from step 1
3. Suspension of solids from step 1 in aqueous
solution
4. Exposure of solids from step 1 to various relative
humidity conditions
• If this program is properly designed, a
polymorph screening study can be executed in
the same sequence of experiments.

Initial Characterization
Characterize each salt product from
the screening study using:
1. Particle morphology (Microscopy)
2. Crystallography (either optical
crystallography or x-ray powder
diffraction)
3. Thermal Methods of Analysis (melting
behavior, DSC, TG)

Further Characterization
For each unique form of the isolated
salts, determine the solubility and
solid-state characteristics:
1. pH dependence of aqueous
solubility
2. Solid-state spectroscopy (FTIR-ATR,
Raman, and/or SS-NMR)
3. Evaluation of hygroscopicity through
exposure to controlled relative
humidities
Summary: What Can You Compute
• Computational programs exist that enable
one to reliably predict a number of chemical
and physical properties of a chemical
substance.
 Ionization constants, Ideal solubility, pH
dependence of distribution coefficient,
etc.
• Therefore, it is relatively easy to predict
whether or not one should prepare a salt
form of a given compound, or whether the
free acid or free base of the substance will
suffice.

Summary: What You Cannot Compute
• It is not yet possible to reliably predict:
– Whether a particular salt will form as a
crystalline substance or as an oil
– The number of polymorphs or solvatomorphs
that can be crystallized for a given salt
– The actual structure of the crystal forms that are
obtained in bulk form
– The physical properties of a particular crystal
form (stability, solubility, dissolution rate,
enantiotropic or monotropic behavior, etc.)