234 The Theory and Practice of Industrial Pharmacy

Table 9.8: Mechanism of An example of the in vivo importance

phase transformations
Mechanism Types of phase transformations in 9.14,
solvate forms is shown Fig.
anhydrous and trihydrate forms of ampicilt
where
Solid-state A-F
Melt A, B and C
were administered orally as a
suspension
tion only), (dehydration/desolva-
D, E, F
human subjects. The more soluble anhydr
(vitrification only) form (10 mg/ml) produced higher and
Solution A-F earlier
peaks in the blood serum levels than the le
Solution A-E, F (amorphous
crystallization soluble trihydrate form.
mediated only); transitions occur only from
the metastable state to the stable
state under the defined conditions
2.11 Ampicillin
Anhydrous
amorphous forms are usually of higher ther- 1.8 Trihydrate
modynamic energy than the
corresponding
crystalline forms, solubilities as well as 1.5
dissolution rates are generally
greater. Upon
storage, amorphous solids tend to revert to
more stable forms. This
thermodynamic insta-
bility, which can ocur during bulk processing 0.9
or within
dosage forms, is a major
disadvan-
tage for developing an amorphous form. .0.6
A crystalline
compound may contain either 0.3
a stoichiometric or non-stoichiometric amount
of crystallization solvent. Non-stoichiometric
adducts, such as inclusions or clathrates, 4
involve entrapped solvent molecules within Hours
the crystal lattice. Usually, this adduct is
undesirable, owing to its lack of
reproduci- Fig. 9.14: Mean serum concentrations of
human subjects after oral administration of ampicilin
in

bility,and should be avoided for

develop- of two solvate forms of the
250 mg doses
ment. A stoichiometric adduct, drug in suspension. Key:
commonly
referred to as a solvate, is a molecular
anhydrous; and o trihydrate
that has incorporated the
complex
crystallizing solvent
molecules into specific sites within the
lattice. When the incorporated solvent is
crystal Polymorphism is the ability of a
compound
(or element) to crystallize as more than one
water, the complex is called a hydrate, and distinct crystalline
species with different
the terms hemihydrate, internal lattices. Chemical
monohydrate,
and stability and
dihydrate describe hydrated forms with molar solubility changes due to polymorphism can
equivalents of water corresponding to half, have an impact on a
drug's bioavailability and
one, and two. A compound not containing its development
program. Chloramphenico
water within its any palmitate exists in three
crystal structure is termed crystalline pol
anhydrous. morphic forms (A, B, and C) and an amor
Identification of possible hydrate com- phous form. Aguiar and co-workers invest
pounds is important since their aqueous gated the relative absorption of polymorpnie
forms A and B from oral
solubilities can be significantly less than their suspensions adm
anhydrous forms. Conversion of an anhy- nistered to human subjects. As summarize
in Fig. 9.15,
drous compound to a hydrate within the "peak" serum levels increaseu
dosage form may reduce the dissolution rate substantially as a function of the percentage
of
and extent of drug absorption.
form B polymorph, the more soluble
polymorph.
 Pretormulation 235

There is no general way of relatinng

24
enantiotropy and monotropy to the properties
of the polymorphs, except by locating the
20 transition temperature or the lack of one. At a
specified pressure, usually 1 atmosphere, the
6 temperature at which two polymorphs have
identical free energies is the transition
12 temperature, and at that temperature, both
forms can coexist and have identical solu-
bilities in any solvent as well as identical
vapour pressures. Below the solid melting
temperatures, the polymorph with the lower
free energy, corresponding to the lower
solubility or vapour pressure, is the thermo-
dynamically stable form.
20 40 60 80 100 During preformulation, it is important to
% Form B identify the polymorph that is stable at room
temperature and to determine whether
Fig.9.15: Correlation of "peak" blood serum levels (2 h) polymorphic transitions are possible within
of chloramphenicol vs percentage of concentration of
polymorph B
the temperature range used for stability
studies and during processing (drying,
Polymorphs can be classified as one of two milling, etc.). As discussed by Haleblian and
types: enantiotropic (one polymorph can be McCrone, a polymorphic compound is best
reversibly changed into another by varying characterized by a complete pressure-tempe-
temperature or pressure, e.g. sulfur) or rature phase diagram showing melt-vapour,
monotropic (one polymorphic form is unstable solid-vapour, and solid-melt curves. A free
at all temperatures and pressures, eg. glyceryl energy-temperature curve at 1 atmosphere
stearates). The thermodynamic difference should be constructed since temperature is
between enatiotropic and monotropic poly- usually a more critical variable than pressure
in pharmaceutics. As previously discussed,
morphic transitions is shown in Table 9.9.
chloramphenicol palmitate has three known
Table 9.9: Thermodynamic difference polymorphic forms, which are thermno-
between polymorphs dynamically described by a van't Hoff plot of
Enantiotropy Monotropy free energy (as determined from solubility
measurements) versus temperature (Fig. 9.16).
Transition melting I Transition >
melting I Transition temperatures are shown by inter-
I Stable > transition I Always stable
section of the extrapolated lines; 50°C for
II Stable < transition forms A and C, and 88°C for forms A and B.
Transition reversible Transition irreversible Form A is the stable form at temperatures less
Solubility I higher Solubility 1 always than 50°C.
<transition lower Transition temperatures obtained by extra-
Solubility I lower polation of van't Hoff plots are susceptible to
transition large errors. Direct measurements of transi-
Transition II > Transition II ->I exo- extrapolated
tions are preferred to support the
I endothermic thermic intersection points in the solubility-tempe-
rature diagrams. The most direct means for
AH <AH" aH>aH
IR peak I before II IR peak I after II determining transition temperatures is
I II Density I > density II microscopic observation of samples held at
Density <
constant temperatures. Unfortunately, these
 236 The Theory and Practice of Industrial Pharmacy

of an analytical method that is sensitive t

small amounts of stable polymorph in th
2 presence of the metastable polymorphs and
excipients. In most cases, the lower limit of
detection for polymorph mixtures is in the
range of 2 to 5%.
To screen for additional polymorphic forms
30 33 36 of a particular drug, bridging solvents,
T10 supersaturated solutions, supercooled melts
and sublimination have proven useful.
Fig.9.16: The van't Hoff plot of solubility vs. reciprocal Observation of the drug particles by light
absolute temperature for microscopy during or atter processing by
polymorphs A, B, and C of
chloramphenicol palmitate. Key: Polymorphs A (A): these techniques should provide substantial
B (o); and C (o) insight into the preferred crystalline forms of
the compound without consuming inordinate
solid-solid or solid-vapour-solid transitions quantities of material.
usually occur slowly, owing to large activation Many
energies and slow nucleation. To facilitate the
physico-chemical properties
with the internal structure of the solid
vary
conversion rate, a single drug,
polymorph or a including melting point, density, hardness,
mixture of forms can be crystal shape, optical properties, and vapour
granulated in a
"bridging" solvent at various temperatures. pressure. Characterization of polymorphic
The drug should be only and solvated forms involves
sparingly soluble in
the bridging solvent, and solvate formation quantitative
analysis of these differing physicochemical
should not occur. These properties. Several methods for studying solid
experiments can be
conducted quickly with a polarizing micro- forms are listed in Table 9.10
Scope, or samples can be stored in sealed
along with the
sample requirements for each test. In the
containers at controlled temperatures and following sections, three of these
periodically examined by other suitable are discussed in detail, with techniques
analytical methods. particular
emphasis on polymorphism.
A more difficult task in the
study of
polymorphism is the determination of the
relative Table 9.10: Analytical methods for
stability of metastable polymorph
and prediction of its rate of conversion within characterization of solid forms
a
dosage form. For suspension dosage forms, Method Material required
the rate of conversion can depend on several per sample
variables, including drug solubility within Microscopy mg
the vehicle, presence of nucleation seed for Fusion methods 1 mg
the stable form, (hot stage microscopy)
temperature, agitation, and
particle size. Solid dosage forms such as Differential scanning 2-5 mg
capsules and tablets have similar compli- calorimetry (DSC/DTA)
cations due to the influence of
particle size, Infrared spectroscopy 2-20 mg
moisture, and excipients. In short, the most
effective means for evaluating the X-ray powder diffraction 500 mg
of a metastable
stability Scanning electron 2 mg
polymorph in the
dosage
form is to initiate prototype formulation microscopy
work by screening a wide range of factors, Thermogravimetric 10 mg
including the presence and absence of seed analysis
crystals of the stable polymorphic form. Dissolution/solubility mg to gm
Essential to this approach is the development analysis
 Preformulation 237

Microscopy: All substances that are trans- light from the microscope to pass through the
parent when examined under a microscope sample. Direct observation by HSM can
that has crossed polarizing filters are either sometimes reveal subtle changes not readily
isotropic or anisotropic. Amorphous sub- detected by the other instrumental techniques.
stances, such as supercooled glasses and
Figure 9.17 shows a simplified schematic
noncrystalline solid organic compounds, or diagram of a HSM. In conjugation with DSC,
substances with cubic crystal lattices, such as HSM facilitates differentiation of DSC endo-
sodium chloride, are isotropic materials, which therms for polymorphic transitions. Figure 9.18
have a single refractive index. With crossed (HSM photographs) and 9.19 (DSC thermo-
polarizing filters, these isotropic substances do gram) shows the sequence of events recorded
not transmit light, and they appear black. on heating a sample of carbamazepine (A). On
Materials with more than one refractive index heating, the sample melted (B) (first endo-
are anisotropic and appear bright with brilliant therm recorded in the DSC thermogram). As
colours (birefringence) against the black the sample was further heated compound
polarized background. The interference colours recrystallized from the melt as acicular crystals
depend upon the crystal thickness and the (C). The acicular crystals continued to grow
differences in refractive indices. Anisotropic until the second crystal form of the compound
substances are either uniaxial, having two melted (D) (second, large endo-therm on the
refractive indices, or biaxial, having three DSC thermogram).
principal refractive indices.
Most drugs are biaxial, corresponding to
Microscope Gas out
either an orthorhombic, monoclinic, or triclinic
Gas in
crystal system. Although one refractive index Window
is easily obtained for biaxial systems, proper
orientation of the crystal along its crystallo-
graphic axes is required to describe the
crystalline form completely. Owing to the
their appea- Heating Window Light Sample
many possible crystal habits and element
rances at different orientations, these methods

require a well-trained optical crystallographer Fig.9.17: Schematic diagram of a hot stage microscopy
to characterize fully even simple biaxial
systems. Crystal morphology differences
between polymorphic forms, however, are
often sufficiently distinct so that the micro-
the less
Scope can be used routinely by
experienced microscopist to describe poly-
morphic crystal habits and observe transitions
induced by heat or solvents. 184.79C 185.9C
Hot-stage Microscopy (HSM): The polari- (B)
(A)
zingmicroscope fitted with a hot stage is a
useful instrument for investigating poly-
morphism, melting points, transition tempe-
controlled
ratures, and rates of transition at
heating rates. HSM is a fusion technique
of
whereby approximately one milligram which
193.5°C 201.4C
material is spread on a microscope slide
(D)
placed on the hot stage and heated.in The
(C)
is then
the
sample can be heated at different
rates
can be microscopic photographs of
sample chamber, and the atmosphereallows the
Fig. 9.18: Hot-stage
carbamazepine
controlled. Sample chamber also
 238 The Theory and Practice of industrial Pharmacy

one polymorph to another may be calculatated

D as shown by Guillory for several sulfona.
mides. Asharp symmetric melting endotherm
15 can indicate relative purity, whereas broad
asymmetric curves suggest impurities or more
0.5 than one thermal process. Heating rate affects
0
-0.5 the kinetics, and hence the apparent tempe-
B
rature of solid-solid transitions.
-1.5 C
A variable with DSC experiments is the
2
-2.5 atmosphere in contact with the sample
30 80 130 180 230 Usually, a continual nitrogen purge is main-
Temperature (°C) tained within the heating chamber; however,
the loss of a volatile counter ion such as
Fig.9.19: DSC thermogram of carbamazepine ethanolamine or acetic acid during a poly
morphic transition may produce misleading
Thermal Analysis: Differential scanning data unless the transition occurs within a
calorimetry (DSC) and differential thermal closed system. In contrast, desolvation of a
analysis (DTA) measure the heat loss or gain dihydrate species, as shown in Fig. 9.20,
resulting from physical or chemical changes releases water vapour, which if unvented can
within a sample as a function of temperature. generate degradation prior to the melting
Examples of endothermic (heat-absorbing) point of the anhydrous form. During initial
processes are fusion, boiling, sublimation, testing, a variety of atmospheres shouldbe
vapourization, desolvation, solid-solid transi tried until the observed thermal process
tions, and chemical degradation. Crystalli- becomes fully understood.
zation and degradation are usually exother- Thermogravimetric analysis (TGA) measures
mic processes. Quantitative measurements of changes in sample weight as a function of time
these processes have many applications in (isothermal) or temperature. Desolvation and
preformulation studies including assessment decomposition processes are
frequently
of purity, polymorphism, solvation, degra- monitored by TGA. Comparing TGA and DSC
dation, and excipient compatibility. data recorded under identical conditions can
For characterizing crystal forms, the heat
greatly aid in the interpretation of thermal
of fusion, AH4, can be obtained from the area- processes. In Fig. 9.20, the dihydrate form ot
under-the-DSC-curve for the melting endo an acetate salt loses two moles of water via an
therm. Similarly, the heat of transition from endothermic transition between 70° and 90°C.

DSC
TGA
Anhydrous form Anhydrous form
100
5
Anhydrous: Dihydrate
90 10:1) Anhydrous: Dihydrate (10:1)
85 Dihydrate form

Dihydrate form
40 50 60 70 80 90 100 110 120130 140 150 160 170
Temperature °C 40 50 60 70 80 90 100 110 120 130 140 150 160 10
Temperature °C
Fig.9.20: Thermogravimetric (TGA) and differential scanning calorimetric (DSC)
analysis for an acetate salt ol d
organic amine that has two crystalline forms, anhydrous and dihydrate.
by dry blending. Heating rate was 5°/min Anhydrous/dihydrate
mixture was prepareo
 Preformulation 239

The second endotherm at 155°C corresponds a given compound. An amorphous form does
to the meiting process, with the accompanying not produce a pattern. Mixtures of different
weight loss due to vapourization ofaceticacid crystalline forms can be analyzed using
as well as to decomposition. normalized intensities at specific angles,
TGA and DSC analysis can also be used to which are unique for each crystalline form. A
quantitate the presence of a solvated species typical standard curve is shown in Fig. 9.22
within a bulk drug sample. For the above for polymorphic forms A and B of chloram-
example, 10% of the dihydrate form was easily phenicol palmitate.
detected by both methods (Fig. 9.20). Both
DSC and TGA are microtechniques and
depend on thermal equilibration within the
sample. Significant variables in these methods
include sample homogeneity, sample size,
particle size, heating rate, sample atmosphere, a5
and sample preparation. Degradation
during
thermal analysis may provide misleading
results, but may be detected by high-per-
formance liquid chromatography (HPLC)
analysis of samples heated under represen-
tative conditions for retention of drug or
appearance of decay products (Fig. 9.21).

DSC 20
AH1 10.45 kcal/M 40 60 80 100
S.D = 2.9 (28%) % Form B3

Fig.9.22: X-ray intensity ratio as a function of composition

of forms A and B of chloramphenicol palmitate

100 Single-crystal X-ray analysis provides

e80 HPLC precise identification and description of a
60
40
crystalline substance. Unit cell dimensions and
angles conclusively establish the crystalline
20
lattice system and provide specific differences
between crystalline forms of a given compound.
50 100 150 200 250
Other methods such as infrared spectroscopy,
Temperature °C
dilatometry, proton magnetic resonance (PMR),
nuclear magnetic resonance spectroscopy
Fig.9.21: Differentialscanning calorimetric (DsC) analysis (NMR), and scanning electron microscopy
and HPLOC stability analysis of an organic amine hydro-
chloride salt that undergoes decomposition upon melting (SEM) have additional applications for studying
polymorphism and solvation.
X-Ray Diffraction: An importanttechnique Infrared (R) Spectroscopy: IR spectroscopy
for establishing the batch-to-batch reprodu- is
also able to distinguish different poly-
cibility of a crystalline form is x-ray powder morphic forms of a compound, since different
diffraction. Random orientation of a crystal arrangements of atoms in solid-state will lead
lattice in a powder sample causes the x-rays
to different molecular environments, and this
to scatter in a reproducible pattern of peak leads to different stretching frequencies. The
intensities at distinct angles (q) relative to the inclusion of solvent or water can be detected
incident beam. Each diffraction pattern is by broad -OH stretch associated with water.
characteristic of a specific crystalline lattice for The use of IR spectroscopy to characterize three
 240 The Theory and Practice of industrial Pharmacy

.Deliquescent: Sufficient water is absorbed

different polymorphic forms of carbamazepine
form a solution.
has been exemplified in Table 9.11.
With most hygroscopic materials, chanoo
in moisture level can greatly intluence any
Hygroscopicity
important parameters,
such as chemical
Many drug
soluble
substances, particularly water-
salt forms, have a tendency to adsorb stability, flowability, and compactibility

atmospheric moisture. Adsorption and (Table 9.12).

equilibrium moisture content can depend To test for hygroscopicity, samples of bulk
upon the atmospheric humidity, temperature, drug are placed in open containers with a thin
surtace area, exposure, and the mechanism of powder bed to assure maximum atmospheric
moisture uptake, as described by Van Campen exposure. These samples are then exposed to
and co-workers. Deliquescent materials a range of controlled relative humidity
adsorb sufficient water to dissolve completely, environments prepared with saturated aqueous
as is observed with sodium chloride on a salt solutions (Table 9.13). Moisture uptake
humid day. Other hygroscopic substances should be monitored at time points represen-
adsorb water because of hydrate formation or tative of handling (0to24 h) and storage (0 to
specific site adsorption. The European 12 weeks). Analytical methods for monitoring
Pharmacopoeia Technical Guide has classified the moisture level (i.e. gravimetry, TGA, Karl
the degree of hygroscopicity into four classes Fischer titration, or gas chromatography)
based on the static method, after storage at depend upon the desired precision and the
25°C for 24 h at 80% RH: amount of moisture adsorbed onto the drug

Slightly hygroscopic: Increase in weight is sample.

20.2 % w/w and < 2 % w/w. Normalized (mg H,O/g sample) or per-
centage-of-weight-gain data from these
Hygroscopic: Increasein weightis 202% w/w
and <15 % w/w. hygroscopic studies are plotted against time
Very hygroscopic: Increase in weight is 2 15% to justify special handling procedures
W/w. kinetically. A plot of normalized equilibrium

Table 9.11: IR bands of Form I, Il and ll of carbamazepine

Carbamazepine N-H stretch C-O-R vibration C-H vibration -C C--C=0
form 3490-3460 cm 1700-1680 cm-1 830-770 cm vibration
Form I 3489 cm 1695 cm1 811, 800, 783 cm Two bands
Form II 3473 cm 1688 cm 815, 783, 770 cm Single band
Form III 3468 cm 1680 cm 810, 775 cm Two bands

Table 9.12: Effect of % relative humidity on appearance and flow property of a compound
%RH Moisture content; (w/w) Appearance and flow properties
0.31 Free-flowing powder, passed easily through sieve
11.3 0.24 Free-flowing powder, passed easily through sieve
22.5 0.27 Less free-flowing powder
38.2 0.32 Base of powder bed adhered to petri dish; however,
material above this flowed
57.6 0.34 Less free-flowing
75.3 0.62 Material caked
Ambient 0.25 Base of powder adhered to petri dish
 Preformulation 241

versus relative humidity data may support the Table 9.14: Particle sizing techniques and
need for storage in a low-humidity environ- size range analyzed
ment or for special packaging with a desiccant.
Method Size range (um)
As these studies proceed, additional
testing Sieving (woven wire) 20-125,000
of powder flow, dissolution, or stability of
"wet" bulk may be warranted to lend further Sieving (electroformed) 5-120
support to the need for humidity controls. Sieving (perforated plate) 1,000-125,000
Microscopy (optical) 0.5-150
Table 9.13: Reiative humidity generated by 0.001-5
various saturaled salt solutions Microscopy (electron)
Sedimentation (gravity) -50
Salt solution % Relative humidity
Sedimentation (centrifugal) 0.01-5
at 25°C
Electrical zone sensing 1-200
Silica gel 0
Potassium acetate
(eg. coulter)
20
Laser-light scattering 1-1,000
Calcium chloride 32
(Fraunhofer)
Sodium bromide 58 0.001-1
Laser light scattering
Potassium bromide 84 (quasi-elastic)
Dipotassium hydrogen 92
phosphate
Kinetic processes involving drug in the solid
Water 100 state, such as dissolution and degradation, may
be more directly related to the available surface
Micromeritic Properties area than to particle size. If drug particles have
Bulk flow, formulation homogeneity, and a shape that can be denned mathematically,
surface area-controlled processes such as then light microscopic size analysis or Coulter
dissolution and chemical reactivity are directly counter analysis with appropriate geometric
affected by micromeritic properties of solids equations may provide a reasonable estimation
such as size, shape, and surface morphology. of the surface area. A more precise measure-
In general, each new drug candidate should ment of surface area is made by Brunauer,
be tested during preformulation with the Emmett, and Teller (BET) nitrogen adsorption,
smallest particle size as is practical to facilitate in which a layer of nitrogen molecules is
the preparation of homogeneous samples and adsorbed to the sample surface at -196°C. Once
maximize the drug's surface area for interac- surface adsorption has reached equilibrium,
tions. The micromeritic properties also have a the sample is heated to room temperature, the
and nitrogen gas is desorbed, and its volume is
significant impact on the processability forms. measured and converted to the number of
product quality pharmaceutical dosage
of
adsorbed molecules via the ideal gas law. Since
Particle Characterization each nitrogen molecule (N2) occupies an area
of 16A, one may readily compute the surface
The techniques most readily available for
area per gram for each preweighed sample.
particle characterization include sievin8
The BET isotherm for pharmaceutical powders
optical microscopy, electron microscopy,
coulter counter and laser diffractometers. is given by:
These techniques are described in detail in
P
Chapter 2. Size characterization is simple for . (18)
spherical particles, but not for irregular
particles where the assigned size will depend
on the method of characterization used. where, P is the partial pressure of the
Table 9.14 lists particle size measurement adsorbate, V is the volume of gas adsorbed at
methods and the corresponding size range. pressure p, Vmon is the volume of gas at mono-
242 The Theory and Practice of industrial Pharmacy

bution, particle shape, and surface ares

layer coverage, P, is the saturation pressure
and c is related to the intercept. Density be defined as ratio of the masa of
can

Thus by plotting P/V (P, - P) versus P/Por an object to its volume;

therefore, the denc:
a straight line of slope C - 1/CVmon and
of a solid is a reflection of the arrangementof
molecules in a solid. Although the mass of a
intercept 1/CVmon will be obtained. The total
bulk powder sample can be determined with
surface area is thus:
measurement of the volume
great accuracy,
is more complicated than it may first appear
S, = NA (19) The main problem arises in actually definine
M
volumes of bulk powders, as may be seen from
where, N is the Arogadro's number, A, is the Fig. 9.23, in which three types of air spaces or
cross-sectional area of the adsorbate and M is voids can be distinguished:
the moleular weight of the adsorbate. It
follows that the specific surface area is given
1. Open intraparticulate voids-those within
a single particle but open to the external
by S,/m, where m is the mass of the sample.
environment.
While BET measurements are usually
2. Closed intraparticulate voids-those within
precise and quickly obtained with current a single particle but closed to the external
commercial equipment, errors may arise from
environment.
the use of impure gases and volatile surface
3. Interparticulate voids-the air spaces
impurities (e.g. hydrates). between individual particles.
Surface morphology may be observed by
scanning electron microscopy (SEM), which
serves to confirm qualitatively a
physical
observation related to surface area. For Inter
example, bulk lots of drug recovered by particulate-
different crystallization processes that have voids
-Open Intra-
been used in an attempt to improve yield may particulate
Closed voids
result in surface morphologies that provide
greater area for surface reactions such as
degradation, dissolution, or hygroscopicity.
During preparation for SEM analysis, the Fig. 9.23: Diagram of various intraparticulate and inter
particulate air spaces in a bed of powder
sample is exposed to high vacuum during the
gold coating process, which is needed to make
the samples conductive, and concomitant Therefore, at least three interpretations of
removal of water or other solvents may result "powder volume" and corresponding "density
in a false picture of the surface morphology. may be proposed:
Variable vacuum treatment of an identical 1. The true volume
(v,)-the total volume of the
sample prior to the gold coating step may solid particles, which excludes all
spaces
confirm the effects of sample preparation on greater than molecular dimensions, and
surface morphology. Most modern SEM which has a characteristic value for each
instruments also provide energy dispersive X- material. The density corresponding to trule
ray spectroscopy analysis of surface metal ions, volume is termed as true density
which may prove beneficial in deciphering an called theoretical
(sometime
density) and defined as
instability or incompatibility problem.
M .. (20)
Density and Porosity
Density and porosity are two important 2.
The granular volume (particle
pharmaceutical properties that can be derived the volumehe
cumulative volume occupied by
from the information on particle size distri
particles, including all intraparticulate (Du
 Preformulation 243

not interparticulate) voids. The density Porosity is frequently expressed as a

corresponding to granular volume is percentage:
termed as granular density and defined as:

P . (21)
E-1001 . (25)

For example, a cylindric tablet of 10 mm

3. The bulk volume (v,)-the total volume diameter and 4 mm height weighed 480 mg
occupied by the entire powder mass under and was made from material of true density
the particular packing achieved during the 1.6 g cm3. The bulk volume v, is given by:
measurement. The density corresponding
to granular volume is termed as V, 10 4
granular
density and defined as: V, = T
10x2 10
(volume of a cylinder is uh)
.(22)
= (0.5)2 x 0.4 0.3142 cm*
where, M is the mass of the sample. The true volume of the solid is the true
Comparing the density p of a sample under density divided by the mass, that is:
specific test conditions with the true of the
material leads to the dimensionless quantity 4801.6=4
1000 1.6
=0.3 cm
p., the relative density, where:
Therefore, the porosity E is:
.(23)
E=100x 0.3 1

During compressional processes, relative

0.3142
= 100(1 - 0.9548)
density increases to a maximum of unity when
all air spaces have been eliminated. = 4.5% (approximately)

Porosity Several practical techniques are available

The voids present in the powder mass may for measuring the density of powder samples.
be more significant than the solid components Apart from X-ray diffraction methods, the
in certain studies. For example, a fine capillary nearest approach to true density is probably
network of voids or pores has been shown to provided by a helium pycnometer. This works
enhance the rate of liquid uptake by tablets, on the principle that within a sealed systen
which in turn increases the rate of their containing helium (a nonadsorbing gas), the
reason, a second
change in pressure caused by a finite change
disintegration. For this in volume of the system is a function of its
dimensionless quantity, the ratio of the total
total volume. A schematic diagram for a
volume of void spaces (vv) to the bulk volume
typical apparatua is shown in Fig. 9.24. During
of the material, is often selected to monitor
operation, the volume of the systen is varied
the progress of compression. This ratio i s
by means of the piston until a preset constant
pressure is produced. This pressure is indi-
referred to as the porosity (E) of the material: cated by the sealed bellows pressure detector,
which integral electrical
V,=Vs-V, .(24) incorporates an
contact. The piston movement (U) necessary
to achieve this pressure is read off from the
Therefore, porosity, E= =1- scale. This value depends on the total volume
V of the system, which in turn is a function of
 44 The Theory and Practice of Industrial Pharmay

density,
special y if
es

measurement
of granule
wet the
Helium liquidsthatcdo
not readily
organic
powde are
used, e.g.
ertain
inert
liqui ds, or
Atmosphere Vacuum Eleçtriçal mercury.
Contact bulk density (g/ml) is
Apparent
presieved (40-mecLter
mined by pouring
into a graduated
cylinder
er via a
lar
bulk
drug the volume and uge
and measuring
determinedeight
funnel
density is
"as is." Tapped
graduated cylinder
Pressure
Sample director placing a containin
o r formulation
Cell
known m a s s of drug a
Variable
volume mechanical tapper apparatus, whichi
number of taps (-1 0
piston operated for a fixed
until the powder bed volume has reacheda
Fig. 9.24: Diagram of a helium pycnometer for minimum. Using the weight of drug in the
determining the true volume of powders. The variable
cylinder and this minimum volume, the
volume piston positions (U,, U, and U,) are read off
from the scale and are used in equation (6) (see text) tapped densitymay be computed. Knowino
the anticipated dose and tapped formulation
density, one may use Fig. 9.25 to determine
the sample volume in the cell. The pycnometer the appropriate size tor a capsule formulation.
is first calibrated using a sample of known
volume v, (usually a stainless steel sphere).
The operating equation for the instrument
000 14
then becomes:
12
V Vx[U-U,] (26) 600 mg 1.0
V,U-U 00
O
8
where, U, Uz and U, are the variable volume 400 mg
scale readings for an empty cell, with standard
volume, and with test powder, respectively.
200 mg
Experimentally, the true density is also
determined by suspending drug particles in
solvents of various densities and in which the 5 6 1 0 1.o 1.1
compound is insoluble. Wetting and pore Packed density (g/ml)
penetration may be enhanced by the addition
of a small quantity of surfactant to the solvent Fig.9.25: Correlation between capsule size and packed
density for different fill weights (200-600 mg)
mixtures. After vigorous agitation, the
samples are centrifuged briefly and then left Powder Flow Properties
to stand undisturbed until floatation or
The flow properties of a material result frou
settling has reached equilibrium. The sample
that remains suspended corresponds to the many forces. Solid particles attract one another,
and forces acting between particles when they
true density of the material. Liquid displace-
are in contact are predominately surface forces
ment by powder pPycnometer (specific There are many types of forces that can a
a

Oravity bottle method) can also be used, but between

unless special precautions are taken to ensure (2) surfacesolid
ces,
particles (1) frictionarces
that no air remains in the sample, the results caused
tension forces, (3) mechanical rar
are prone to errors. For this reason,
by interlocking of particles ot irreBe
best
liquid shape, (4) electrostatic forces and (5) cohe
displacement is probably regarded as a of these forces
or Van der Waals forces. All
 Preformulation 245

can affect flow

ceutical powders
properties of a solid. Pharma- Table 9.15: Scale of fowability for Carr's
may be broadly classified as compressibility index and Hausner's ratio
free-flowing or cohesive (non-free-flowing). Carr's Hausner's Flowability
Most flow
properties are significantly affected index ratio
by changes in particle size, density, shape,
electrostatic charge, and adsorbed moisture, 5-15 1.05 1.18 Excellent
which may arise from 1.14 1.20 Good
tion. As a result, a
processing or formula- 12-16
free-flowing drug candidate 18-21 1.22 1.26 Fair-passable
may become cohesive during
thus development, 23-35 1.30 1.54 Poor
necessitating an entirely new formulation 33-38 1.50 1.61 Very poor
strategy. Preformulation powder flow investi-
gations should quantitatively assess the >40 >1.67 Very, very poor
pharmaceutical consequences of each process
improvement and provide direction for the sizes ( to inches) should be made. In
formulation development project team. This
general, the greater the standard deviation
direction may consist of a formulation recom-
between multiple flow rate measurements, the
mendation such as granulation or densification
greater is the weight variation in products
via slugging, the need for special auger feed
produced from that powder. When several
equipment, or a test system for evaluating the
lots of a drug candidate are tested under
improvements in flow brought about by
dissimilar conditions, Eq. (1), proposed by
formulation. This subject becomes paramount
Jones and Pilpel, may be used to show the
when attempting to develop a commercial solid
dependence of flow rate (W) on true particle
dosage form containing a large percentage of
density (p), acceleration due to gravity (g), and
cohesive material.
orifice diameter (D). Both (A) and (n) are
A simple indication of the ease with which constants that are dependent upon the
a material can be induced to flow is
given by material and its particle size.
application of a compressibility index and
Hausner ratio given by the equation:
D, =A 4W . (29)
Carr's compressibility index 607p8
(Tap density - Bulk density)1og%
.

(27) Angles of Repose

Tap density A simple practical technique for measuring
resistance to particle movemernt is a quantity
Hausner's ratio = Tapdensity .(28)
BulkBulk density called the angle of repose of a powder. This is
the angle, 8 as defined by the equation:

Scale of flowability for Carr's compressi-

tan 2 . (30)
bility index and Hausner's ratio is given in
Table 9.15, whereas, Table 9.16 lists compressi-
bility data and flowability characterization for It is the maximum angle that can be
several pharmaceutical excipients. obtained between the freestanding surface of
Alternatively, free-flowing powders may be a powder heap and the horizontal plane, as
characterized by a simple flow rate apparatus shown in Fig. 9.26A. Such measurements give
consisting of a grounded metal tube from at least a qualitative assessment of the internal
which drug flows through an orifice onto an cohesive and frictional effects under low levels
electronic balance, which is connected to a ofexternal loading, as might apply in powder
strip chart recorder. Several flow rate. (g/s) mixing, or in tablet die or capsule shell filling
determinations at each of a variety of orifice operations
 246 The
Theory and Practie of Industrial Pharmacy

Tab 9.16: Compressibility and flowability of pharmaceutical excipients

Material
Celutab
%Compressibility
Flowability
Excellent
Emcompress
Star X-1500
15 Excellent
Lactose nmonohydrate
19
Fair-passable
Maize starch 26-2/
19
Fair-passable
Poor
Dicalcium phosphate, 27 Poor
dihydrate (coarse)
Magnesium stearate 31 Poor
Titanium dioxide 34 Very poor
Dicalcium phosphate, dihydrate (fine)
Talc
41 Very, very poor
49 Very, very poor

repose angle is calculated as before. Anlo

repose methods, which result in
so-called a
dynamic angle, are preterred, since they mos
closely mimic the manutacturing situation, in
which the powder is in motion.
(A) A
Kinetic or Dynamic Angle of Repose
Rotating Cylinder Method
A typical dynamic test involves a hollow
B
(C)
cylinder half-filled with the test
powder, with
one end sealed by a
transparent plate. The
Fig. 9.26: Measurement of dynamic angles of repose, cylinder isrotated about its horizontal axis
6, as defined from the dimensions of a conical bed of (Fig. 9.26B), until the powder surface cascades.
the powder (A), where tan6= The curved wall is lined with
twice the powder bed
(h)/powder bed diameter (D). (B and C) representheight the
sandpaper to
prevent preferential slip at this surface.
rotating cylinder and tilted box methods of measurement,
respectively
Tilting Box Method
Static Angle of Repose A
sandpaper-lined rectangular box is filled
with the powder and
The fixed funnel method
employs a funnel
contents
carefully tilted until the
that is secured with its
tip at a begin to slide, as shown in
Fig. 9.260.
H, above graph paper that is givenonheight, The maximum angle that the plane of
placed a flat makes with the horizontal powder
horizontal surface. Powder or surface on rotation
carefully poured through the funnel granulation is is taken as the angle of
of
until the
rarely less than
repose.Values
ot P are
apex the conical pile just touches the tip of indicate 20°, and values of up to 4
the funnel. The diameter of the reasonable flow potential. Above 5u
base of the
conical pile is then determined to calculate however, the powder flows only with great
the
angle of repose. difficulty, if at all. Values for angles ot reps
The fixed cone method
establishes the S30and
usually indicate a free-flowing materia
diameter of the cone base, D,
by angles 240° suggest a poorly flown
circular dish with sharp edges. Powder is using a
material. As mentioned of

poured onto the center of the dish from a coarse previously,

particles is also related to pack tro
funnel that can be raised densities and mechanical
tically until a particles. For
maximunm cone height, H, is obtained. The to this reason, a ood auxiliary test
arrangemen
run in goo
conjunction with the angle of rep pOse
 Preformulation 247

test is the
compressibility test, discussed Hydrolysis
previously (Fig. 9.27). From the angle of Many pharamaceuticals contain ester or
repose and compressibility values, a reaso- amide functional groups, which undergo
nable indication of a material's inherent flow
properties should be possible. hydrolysis in solution. Examples of drugs that
tend to degrade by hydrolytic cleavage of an
ester or amide linkage are anesthetics, anti-
biotics, vitamins, and barbiturates.
30
Ester Hydrolysis
Poor intomixture of
The hydrolysis of an ester a

Very poor flow acid and alcohol essentially involves the

20T (flooding)
an

rupture of a covalent linkage between a

Fair carbon atom and an oxygen atom. Although
some of these hydrolyses can be effected
in
Good
10T the
pure water, in the majority of cases,
presence of catalyst is needed to promote
the
Excellent reaction. These catalysts are invariably sub-
flow stances of polar nature, such as mineral acids,
10 20 30 40
Angle of repose (0) alkalies, or certain enzymes, all of which are
capable of supplying hydrogen or hydroxyl
Fig.9.27: Relationship between angle of repose, Carr's
ions to the reaction mixture.
index and flow characteristics of powder
In practice, the general scheme employed
to denote ester hydrolysis is as follows:
Stability Analysis
Preformulation stability studies are usually
the first quantitative assessment of chemical R'-C-OR+ H* +OH R-C-OH HOR
stability of a new drug. These studies include ester acid alcoho!
both solution and solid-state experiments
under conditions typical for the handling,
formulation, storage, and administration of a Amide Hydrolysis
drug candidate. Pharmaceutical compounds containing an
Knowledge about the stability ot a candi- amide group can undergo hydrolysis in a
date drug in the solid and liquid state is manner similar to that of an ester-type
extremely important in drug development. In compound. Instead of the acid and alcohol that
the longer term, the stability of the formu- form as a result of ester hydrolysis, hydrolytic
lation will dictate the shelf-life of the marketed cleavage of an amide results in the formation
product, however, to achieve this, careful of an acid and an amine.
preformulation is required. The major objec-
tives of the preformulation team are, therefore,
to identify conditions to which the compound
R-C-N-R'+H+0H R-C-OH H,N-R
is sensitive and interpret degradation profiles amide acid amine
under these conditions. The major routes of
are via hydro-
drug degradation in solution reactions. Because of the relatively greater stability of
lysis, oxidation or photochemical
amides as compared with structurally-similar
Solution Stability esters, there is considerably less information in
the literature on quantitative chemical kinetic
The decomposition of a drug occurs through studies pertaining to the hydrolytic stability of
several pathways, i.e., hydrolysis, oxidation,
photolysis and racemization. such compounds. Pharmaceuticals such as
248
The Theory?and Practice of industriel Pharmacy

to the stability of
amide, phenethicillin, barbiturates, and
chloramp
important

formulations, since the biologic

be considerably
armaceut
ftect of the
degrade by amide hydrolysis. can
lesst
Oxidation
dextro-form
the levo form.
For example, levo-. than that
The oxidative decomp
mposition of arma
of
is 15 to 20
times m o r e active than
adrenaline. Solutions of levo-adrena
adrenaline
Ceutical compounds is responsiblephar
ror the mixture of equal parts of | ine form
nstability of considerable number
a
a
racemic
dextro-adrenaline with a pharm \evo- and
pharmaceutical preparations. For e activity just
over half that of the
steroids, vitamins, antibiotics, and pure levo,
phrine undergo
oxidative degradation.
epr 1ne
compound.
of this
most common form of oxidative decom The primary objective phase
preformulation research is of
pOSition
tions is occurring
in
pharmaceutical prepard to form ntification
autoxidation,
radical chain which involves a rec
of conditions necessary
solution. These studies should inclu
a stable

process. In
may be defined as the general, autoxidation effects of pH, ionic strength, cosolvente
With reaction of
molecular oxvgen. Free radicals
materlal
any temperature, and oxygen. light,
lution stabil
produced are
by reactions involving homolytic investigations usually commencewiith
bond fission of a
covalent bond, so that each probing experiments to confir decay at the
atom or
group involved retains one of the extremes of pH and temperature
electrons of the original covalent bond. To test HCl, water, and 0.I NNaOH all at (e.g. 0.1N
whether a 90°C). These
compound is sensitive to oxygen intentionally- degraded samples may be used
simply bubble air through the solution, or add to confirm assay specificity as well as to
hydrogen peroxide, and assess the amount of provide estimates tor maximum rates of
degradation that takes place. degradation. This initial experiment should be
followed by the generation of a complete pH.
Photolysis profile to identify the pH of maximum
rate
Consideration of the
decomposition of stability. Aqueous buffers are used to produce
pharmaceutical compounds resulting from solutions over a wide range of pH values with
the absorption of radiant in the form constant levels of drug, cosolvent, and ionic
of light has become more
energy
important in recent strength.
years because of the complex chemical Since most solution
intended for parenteralpharmaceuticals
are
structure of many new
drugs. Degradative routes of adminis-
reactions, such as oxidation-reduction, ring tration, this initial pH-rate study should be
rearrangement, or modification and polymeri- conducted at a constant ionic
zation, can be brought about by exposure to strength that is
compatible with physiologic media. The ionic
light at particular wavelengths. According to strength (u) of an isotonic 0.9% sodium
the equation, E 2.859 x 10°/A kcal
=
chloride solution is 0.15, and
per mole, several com-
the shorter the wavelength (A) of
light, the pendia contain formulae for isotonic buffer
more energy (E) is absorbed per mole. solutions. lonic
Consequently, the radiations absorbed from the strength for any new butter
solution may be calculated
ultraviolet and violet portions of the light from the following
equation:
spectrum are more active in initiating chemical
reactions than those absorbed from the other
longer wavelength portions of the spectrum. mZ . (31)

Racemization where, n,(is the molar the

In such a reaction, an optically-active substanco
1on concentration or
having valency, Z,. Note that all 10n
a

loses its optical activity without changing its Species (even the drug molecules)
in a
chemical composition. This reaction can be Solution must be bune
ionic strength. considered in computing
 Preformulation 249

Once the stability solutions

aliquots
are
prepared,
are
placed in flint
glass ampules, -06t
flame-sealed to prevent evaporation, and
stored at constant temperatures not exceeding
the boiling point of the most volatile cosolvent - 1.0F
or its azeotrope. Some of the
ampules may be - 1.4
stored at a wide range of temperatures to
provide data for calculating activation energies.
Some of these solution 1.8
samples should be
subjected to a light stability test, which includes
protective packaging in amber and yellow 2.2
greenglass containers. Control samples for this
light test may be stored in cardboard packages - 2.6

or wrapped in aluminum foil.

Given that the potential for oxidation is - 3.0

initially unknown, some of the solution 1.0 3.0 5.0 7.0 9.0
samples should also be subjected to further pH
testing (1) with an excessive headspace of
Oxygen, (2) with a headspace of an inert gas
such as helium or nitrogen, (3) with an Fig. 9.28: The pH-rate profiles for ampicillin degradation
in solution at 35°C and constant ionic strength (u = 0.5).
inorganic antioxidant such as sodium meta- Dotted line is the apparent rate profile in the presence
bisulfite, and (4) with an organic antioxidant of buffer, while the solid line is the theoretic rate profile
such as butylated hydroxytoluene (BHT). at zero buffer concentration
Headspace composition can be controlled if
the samples are stored in vials for injection approach the anticipated "use" temperature.
that are capped with Teflon-coated rubber If this relationship is linear, one may assume
stoppers. After penetrating the stoppers with a constant
decay mechanismover this tempe-
needles, the headspace is flooded with the rature range and calculate an activation energy
desired atmosphere, and the resulting needle (E) from the slope (-E,/R) of the line as
holes are sealed with wax to prevent degassing. described following equation:
To generate a pH-rate profile, stability data
generated at each pH and temperature
condition are analyzed kinetically to yield the k .c .(32)
apparent decay rate constants. All of the rate
constants at a single temperature are then where, C is a constant of integration and R is
plotted as a function of pH as shown in the gas constant.
Fig. 9.28. The minimum in this curve is the pH A broken or non-linear Arrhenius plot
of maximum stability. Often, this plot, as it suggests a change in the rate-limiting step of
approaches its limits, provides insight into the the reaction ora change in decay mechanism,
molecular involvement of hydrogen or thus making extrapolation unreliable. In a
hydroxide ions in the decay mechanism. solution-state oxidation reaction, for example,
An Arrhenius plot is constructed by plotting the apparent decay rate constant decreases with
the logarithm of the apparent decay rate elevation of temperature because the solubility
constant versus the reciprocal of the absolute of oxygen in water decreases. At elevated
temperature which each particular buffer
at
temperatures, excipients or buffers may also
solution was stored during the stability test. degrade to give products that are incompatible
To justify extrapolation to "use" conditions, with the drug under study. Often, inspection
stability storage temperatures should be of the HPLC chromatograms for decay products
selected that incrementally (At - 10°C) confirms a change in the decay mechanism.
 250 The Theory and Practice of Industrial Pharmacy

Shelf-life (t1o.) for a drug at "use" conditions analytic data from such studies
ies as TLC,
may be calculated from the appropriate kinetic fluorescence, or UV/Visible spectrosco
equation, and the decay rate constant obtained be required to determine precisely the i
from the Arrhenius plot. For a first-order decay of decay product{s) appearance, and
process, shelf-life is computed from: establish a room-temperature shelf-life for
drug candidate.
the
In 0.90 0.105 the many
To study possible solid-stato
-

t10% . (33)
k reactions, one may need more than a specife
k
assay for the intact compound. Polymorphic
where, fo. is the time for 10% decay to occur
changes, for example, are usually detected h
with apparent first-order decay constant k.
Frequently, it is useful to present the pH-rate
or
quantitative infrared analysis (IR). In th
as a plot of
case of surface discolouration due to oxidation
profile pH versus ho, shelf-life or reaction with excipients, surface
data. reflectance
measurements on tristimulus or diffuse
Results of these initial solution stability
reflectance equipment may be more sensitive
studies dictate the subsequent course of action.
If the compound is sufficiently stable, than HPLC assay. In any event, additional
liquid samples are required in the solid-state stability
formulation development may commence at
study to accommodate these additional test.
once. If the compound is unstable, then further To determine the solid-state stability profile
investigations may be necessary.
of a new compound, weighed samples are
Solid-state Stability placed in open screw-cap vials and are
The primary objectives of this exposed directly to a variety of temperatures,
investigation humidities, and light intensities for up to 12
are identification of stable storage conditions
for drug in the solid state and identification weeks (Fig. 9.29). Samples usually consist of
of compatible excipients for a formulation. three 5- to 10 mg weighed samples at each
data point for HPLC
Contrary to the earlier solution stability analysis and approxi-
profile, these solid state studies may be mately 10 to 50 mg of sample for polymorph
severely affected by changes in purity and evaluation by DSC and IR (-2 mg in KBr and
20 mg in Nujol). To test for surface oxidation,
crystallinity, which often result from process
improvements. Repetitive testing of the initial
bulk lot in parallel with newer bulk lots should Storage condition 4 weeks 8 weeks 12 weeks
be performed, and adequate material should
be set aside for these studies.
5°C-(Refrigerator)
22°C-(Room temperature)
In general, solid-state reactions are much 37°C-Ambient humidity
slower and more difficult to 37°C/75% RH
interpret
than
solution-state reactions, owing to a reduced Light box
number of molecular contacts between Clear glass
and excipient molecules and to the drug Amber glass
occurrence
of multiple-phase reactions. A kinetic Yellow-green glass
of slow solid-state analysis No exposure (control)
degradation
retention of intact drug may fail to
based on 50°C-Ambient humidity
clearly the compound's shelf-life,quantitate
- O2 H e a d s p a c e

as
variation may equal or exceed the assay
- Ng Headspace

limited 70°C-Ambient humidity

apparent degradation, particularly at the low 90°C-Ambient humidity
temperatures that are critical to establishing
a
room-temperature shelf-life. Fig. 9.29: Sample
situation may be corrected on Usually,of this scheme for determining the bulk
stability profile for a new drug candidate. At each poin
analysis the
appearance of decay product(s), which may bulk drug samples should consist of 3 x 10 mg for HPLC
total only 1 to 5% of the analysis and a 50 mg sample for polymorph analysis y
sample. Additional DSC or IR
 Preformulation 251

samples are stored in large (25 ml) vials for Another useful relationship for analyzing
injection, capped with a Teflon-lined rubber solid-state stability data assumes that a
stopper and the headspace flooded with dry compound must partially liquefy prior to
oxygen. To confirm that the decay observed is
decomposition. Given that the mole fraction
due solely to oxygen rather than to reduced of the solid that has liquefied (Fm) is directly
humidity, a second set of vials should be tested proportional to its decay rate, then:
in which the atmosphere is flooded with
dry
nitrogen. After a fixed exposure time, these
samples are removed and analyzed by multiple I nk I n F, =- -AH1
R T .. (35)
methods to check for chemical stability,
polymorphic changes, and discolouration.
where, AHus is the molar heat of fusion, Tm is
Once the results of this initial screen are
the absolute melting point (°kelvin), T is the
tabulated, the decay process may be analyzed absolute temperature of the stability study,
by either zero-order or first-order kinetics,
and R is the gas constant.
particularly if the amount of decay is less than
Once the bulk drug stability has been
15 to 20%. The same kinetic order should be
used to analyze the data at each temperature, determined, compatibility with excipients
commonly used to produce solid dosage
if possible. Samples exposed to oxygen, light,
and humidity may suggest the need for a forms must be established.
follow up stability test at three or more levels
Drug-excipient Compatibility
of a given parameter for full quantitation of
its involvement. The successful formulation of a stable and
effective dosage form depends not only on the
In the event that humidity is not a factor in
active pharmaceutical ingredient but also on
drug stability, an Arrhenius plot may be
the careful selection of excipients. The proper
constructed, and if linear, it may be extra-
selection of excipients is vital in the design of
polated to "use" conditions for predicting a quality drug product. Selection of the
shelf-life. If humidity directly affects drug excipients and their concentration in a
stability, the concentration of water in the formulation is based not only on their
atmosphere may be determined from the functionality, but also on the compatibility
relative humidity and temperature by using between the drug and excipients. An incom-
psychrometric charts. Stability data obtained patibility may result in changes in physical,
at various humidities may be linearized w.r.t. chemical, microbiological or therapeutic
moisture using the following apparent decay properties of the dosage form.
rate constant:
Drug-excipient compatibility studies are
conducted mainly to predict the potential
ku Lxplko .. (34)
incompatibility, and to provide justification for
where, Igp/] is the concentration of water in the selection of excipients in the formulation
as required in
the atmosphere in units of grams of water per regulatory filings. Knowledge
liter of dry air, and ko is the decay rate constant gained from drug-excipient compatibility
at zero relative humidity. For example, a 75% studies is important in the drug development
relative humidity atmosphere at 37°C is process, is used to select the dosage form
equivalent to 0.0405 grams of water per liter components, delineate stability profile of the
(gpl) of dry air. When the effect of moisture drug, identify degradation products, and to
on chemical stability is examined in detail, a understand the mechanisms of reactions.

comparison to solution-state stability and Drug-excipient studies are usually con-

hygroscopicity data may suggest an aqueous ducted after gaining an understanding of
reaction occurring in the drug-saturated water solution- and solid-state stability, but before
layer on the crystal surface. the formulation development activities.
 252 The Theory and Practice of industrial Pharmacy

An incompatibility in the dosage form can neutral glass ampoules and half of the
result in any of the following changes: ampoules are sealed without further treat-
ment. To the other, 5% distilled water is
Changes in organoleptic properties added
prior to sealing. Alternatively, the drug in
Changes in dissolution performance
suspension with excipients may be investi.
Physical form conversion
gated. The ampoules are then stored at a
An decrease in potency suitable temperature and analyzed at various
An increase in degradation products.
time points. The storage conditions used to
Several examples of incompatibilities in examine compatibility can vary widely in
pharmaceutical excipients are known in the terms of temperature and humidity, but a
literature and can be used as a guiding temperature of 50°C for storage of compati
reference (Table 9.17). Some examples of bility samples is considered appropriate. Some
reactions of pharmaceutical excipients or their compounds may require higher temperatures
impurities with drugs are shown in Fig. 9.30. to make reactions proceed at a rate that can
be measured over a convenient time period.
Method Figure 9.31 shows a representative of multiple
A binary mixture of drug with the excipient drug-excipient compatibility testing protocol.
Methods of analysis also vary widely,
being investigated is intimately mixed, the
ratio of drug to excipient often being 1:1; ranging from thermal techniques (DSC), to
however, other rates may also be investigated. chromatographic techniques (TLC, HPLC), to
Powder samples are then dispensed into clear, microcalorimetry. DSC has been used exten-

Table 9.17: Incompatibilities due to pharmaceutical excipients

Excipient Incompatibility
Lactose
Maillard reactions, Claissen-Schmidt condensation reaction of
its impurity 5-hydroxylmethyl-2-furfuraldehyde, and catalysis.

Microcrystalline cellulose Maillard reaction, water sorption resulting in increased

hydrolysis, adsorption of basic drugs, and non-specific incompati-
bilities due to hydrogen bonding capability.
Oxidation attributable to peroxides, nucleophilic addition too
Povidone and crospovidone
amino acids and peptides, and hydrolysis of sensitive drugs due
to moisture.
Hydroxypropyl cellulose Oxidation of sensitive drugs due to residual peroides.
Croscarmellose sodium Weakly basic drugs can compete with the sodium counter-ion
thus getting adsorbed, drug salt-form conversion.
of and their salts due to
weakly-basic drugs
Sodium starch glycolate Adsorption
electrostatic interactions, residual monochloroacetate may
undergo nucleophilic reactions.
to react with the
Starch Terminal aldehydes in starch have been known
hydrazine moiety, moisture-mediated reactions, drug adsorbtion
and may react with formaldehyde resulting in reduced tunc
tionality as a disintegrant.
and may
Colloidal silicon dioxide May act as a Lewis acid under anhydrous conditions,
adsorb drugs.
Magnesium stearate Exists in hydration states: mono, di and trihydrates, Mg
a basic p
impurity is known to react with ibuprofen, provides and
environment and accelerate hydrolytic degradation,
magnesium metal may also cause chelation-induced degradation
 Preformulation 253

OH
NHR,
OH
H

R,NH,+H OH NHR,

Amine A R
Reducing
sugar NHR1 Amadori
-OH
product
H

NR +H-O-0-H OH

Hydrogen N-oxide
peroxide

-OH

OH
OH
Lactose impurity OH

Haloperidol

R,-NHOH

R-NH2+ R2
H H
R-N=CH
R-

NR
+H-O-O-H
OH
Hydrogen N-oxide
peroxide

Fig. 9.30: Reactions of pharmaceutical excipients or their impurities with drugs

 254 The Theory and Practice of Industrial Pharmacy

Compatibility protocol
Experiment
1 2 8 9 10 11 12 13 14 15
16 170
Drug substance 200 25 25 25 25 25 25 25 25 25
Lactose
25 25 25
170
25
175 170 170
Mannitol 175 170 170 170
Microcrystalline
cellulose 170
175 170 170
Dibasic calcium
phosphate dihydrate 175 170 170 170
Magnesium stearate 5 5 5
Sodium stearyl
fumarate 5 5 5 5
Stearic acid 5 5
Fig. 9.31: Protocol of multiple drug-excipient compatibility study

Drug

No interaction

50%mixtureH DSC
Recommend
excipient
Interaction
Excipient
TLC

Alternative
Significant No
excipient? breakdown?

Fig. 9.32: Scheme to identify chemically compatible excipients

sively for compatibility studies. Although only micelle concentration of the formulations. For
milligram quantities of drug are needed for a preparations for oral use, compatibility testing
DSC experiment, the
interpretation of the with ethanol, glycerine, syrup, sucrosSe,
thermograms may be difficult, and conclusions butters and preservatives are carried out to
may be misleading on the basis of DSC have an idea about the activation energy or
experiments alone. A scheme for interpreting the predominant reaction in solution.
drug-excipient compatibility data is shown in
Fig. 9.32. Depending on the number of
excipients to be
investigated, compatibility Formulation Recommendation
tests can be speeded
up by using factorial or Upon
reduced factorial design experiments. completion of the preformulation
evaluation of a new drug candidate, it
is
Liquid Compatibilities recommended that a comprehensive rep tbe
In general, such studies prepared highlighting the pharmaceutica
are
placing the drug in a solution of the additive.
performed by problems associated with this molecule. 1his

Usually, both amber and flint vials are used report should conclude with recommet
and in many autoclaved
dations for developing phase I formulations.
cases conditions are These in
included. In case of emulsions, the preformu- reportsextremely importaaid
are
n
lation studies include measuring the critical preparing regulatory documents, and
developing subsequent drug candidates