AquaSolve As Handbook

AquaSolve and
AquaSolve AS
hydroxypropylmethylcellulose acetate succinate
Physical and chemical properties

handbook
With good chemistry great things happen.
Table of Contents
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
CHEMISTRY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Origin6
Manufacturing
Grades and Types
PHYSICOCHEMICAL PROPERTIES . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Product Specifications
Morphology
Moisture Absorption
Thermal Properties
Glass Transition Temperature
Thermal Decomposition Temperature
Melt Viscosity
Melt Viscosity with Various Plasticizers
Viscosity in Various Solvents
Solubility at Various pH
Film Strength
APPLICATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Solid Dispersion for Bioavailability Enhancement
Enteric Coating
INCOMPATIBILITIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15
STABILITY AND STORAGE CONDITIONS . . . . . . . . . . . . . . . . . . . .15
PACKAGING AND SHIPPING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
REGULATORY STATUS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15
TOXICOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
AquaSolve and AquaSolve AS Hydroxypropylmethylcellulose Acetate Succinate
Introduction
AquaSolve (AquaSolve AS in the United Kingdom)

hydroxypropylmethylcellulose acetate succinate (HPMCAS; known
as hypromellose acetate succinate in pharmaceutical applications)
is a mixture of acetic acid and monosuccinic acid esters of
hydroxypropylmethyl cellulose in the form of a white to off-white
powder or granules. It has a faint acetic acid-like odor and a barely
detectable taste. AquaSolve HPMCAS is available in several grades
varying in extent of substitution of acetyl and succinoyl groups and
in particle size (fine or granular).
AquaSolve HPMCAS has the following functions and properties:
AquaSolve HPMCAS can be used as a solid-dispersion carrier for

bioavailability enhancement of poorly soluble compounds. It is
insoluble in gastric fluid, but will swell and dissolve rapidly in the
upper small intestine. AquaSolve HPMCAS is commonly used as
an enteric film-coating agent for tablets, capsules and granules.
For aqueous film-coating purposes, a dispersion of HPMCAS
fine powder and plasticizer (such as triethyl citrate) in water is
commonly used. AquaSolve HPMCAS is also used in preparation of
sustained drug-release formulations. The release rate of the model
drug from the matrix is pH dependent. Other formulation options
include neutralized-solution/organic-solvent applications and drypowder coating.
It is an enteric coating polymer.
It is practically insoluble in water, ethanol and hexane.

It may have a faint acetic acid-like odor.
It is tasteless.
It is physiologically inert.
It is a preferred solid-dispersion carrier for bioavailability
enhancement.
These properties and functions make it suitable for use in many

pharmaceutical applications. The polymer is available in three
grades: L, M and H, based on the content of acetyl and succinoyl
groups (wt%) in the HPMCAS molecule. Each grade is available in
two different particle sizes, F (fine) and G (granular).
This handbook describes basic chemical and physical properties of
AquaSolve HPMCAS. The range of types produced and the typical
uses for this versatile cellulosic enteric polymer are also discussed.
Chemistry
Figure 1 shows the structure of the HPMCAS molecule; it is

visualized as a polymer chain composed of 2-hydroxypropoxy
groups (-OCH2CH(CH3)OH), methoxy groups (-OCH3), acetyl groups
(-COCH3), and succinoyl groups (-COCH2CH2COOH).
CASRN:
71138-97-1
CAS Name: Cellulose, 2-hydroxypropyl methyl ether, acetate

hydrogen butanedioate
Figure 1 Structure of hydroxypropylmethylcellulose acetate
succinate
RO
O
RO
OR
O
RO
O
RO
O
OR
n
R=
H
CH3
C(O)CH3
[CH2CH(CH3)O]mR1
R1=
H
CH3
C(O)CH3
C(O)CH2CH2CO2H
Manufacturing
Acetic anhydride and succinic anhydride are reacted with
hydroxypropylmethylcellulose (HPMC) under specifically controlled
conditions to produce AquaSolve HPMCAS. The process begins
with cellulose, a polymer chain composed of repeating -1,4anhydroglucose units. Each anhydroglucose unit contains three
hydroxyl groups. The hydroxyl groups of HPMC used to make
HPMCAS are substituted with specific levels of methoxyl and
hydroxypropoxy groups. The degree of substitution (DS) of
methoxyl on HPMC ranges from 1.78 to 2.02 while the molar
substitution of hydroxypropoxy is 0.23 to 0.41. The methoxyl DS
influences the amount of free hydroxyl groups available for further
substitution. Because the hydroxypropoxy group by definition
contains a hydroxyl substitution, the level of hydroxypropoxy
substitution does not change the overall number of hydroxyl
groups available for further substitution. When HPMC is reacted
with defined quantities and ratios of acetic anhydride and succinic
anhydride, HPMCAS is produced, containing various levels of acetyl
and succinoyl esters.
Grades and Types

AquaSolve HPMCAS is produced in three substitution grades: L, M
and H. The three grades are insoluble in acidic aqueous solutions.
All three grades are soluble in dilute caustic solution, and to various
degrees in acetone and methanol. Each grade is available in fine (F)
and granular (G) particle sizes. The range of grades is listed in Table
1, according to the content of acetyl groups. The contents of the
other major substituent groups are also listed in the table. Unless
otherwise noted, all percentages in this text are percentages by
weight.
C(O)CH2CH2CO2H
Table 1 AquaSolve HPMCAS grades
Origin
AquaSolve HPMCAS is a synthetic polymer derived from cellulose,
the most abundant polymer in nature. Highly purified cellulose pulp
is reacted with methyl chloride and propylene oxide under alkaline
conditions to produce hydroxypropylmethylcellulose (HPMC). The
HPMC is then used in a chemical sequence to produce AquaSolve
HPMCAS by reaction with acetic anhydride and succinic anhydride.
Grade
Acetyl
Content
Succinoyl
Content
Methoxyl
Content
Hydroxypropoxy
Content
59%
1418%
2024%
59%
711
1014%
2125%
59%
1014%
48%
2226%
610%
Physicochemical Properties
Figure 2 shows the available grades of AquaSolve HPMCAS plotted

by range of acetyl and succinoyl substitution levels.
Product Specifications
Figure 2 Available grades of AquaSolve HPMCAS
Table 2 Product specifications
Detailed product specifications are listed in Table 2.
30
AquaSolve AS HPMCAS
LF and LG
28
26
Methoxyl range:
12-28%
Hydroxypropoxy range: 4-28%
24
Succinoyl Content (wt%)
22
16
L Grade
14
12
M Grade
Identification
Conforms to U.S. National Formulary and

Japanese Pharmacopoeia monographs
H Grade
4
2
0
10
5%
Residue on Ignition
0.20%
Heavy Metals
< 10 ppm
Arsenic
2 ppm
Acetyl Content
12
14
16
18
20
Acetyl Content (wt%)

AquaSolve HPMCAS complies with National Formulary and Japanese Pharmaceutical
Excipients specifications (shaded box)
1
1.0%
59%
711%
1014%
Succinoyl Content
1418%
1014%
48%
Methoxyl Content
2024%
2125%
2226%
Hydroxypropoxy
Content
59%
59%
610%
Average Particle Size

(Laser Diffraction) F
Types
10 microns
D90 (Laser
Diffraction) F Types
20 microns
Measured for a 2% solution at 20C.
Ashland can tailor certain chemical and physical properties of

AquaSolve HPMCAS to meet users unique requirements. Users
are encouraged to discuss their needs with their Ashland technical
representative, or to call the toll-free number shown on the back
cover of this booklet for product information.
2.43.6 mPas
Limit of Free Succinic

and Acetic Acids
10
White to off-white powder (F) or granules (G)
Loss on Drying
18
HF and HG
Appearance
Viscosity1
20
MF and MG
Morphology
The fine grind grades of AquaSolve HPMCAS are rounded to
elongated particles ranging from approximately 0.50 to 1.50
microns in diameter mixed with elongated to rounded fairly dense
agglomerates ranging up to around 10.0 microns in diameter. The
coarse grind grades of AquaSolve HPMCAS consist of large, fairly
dense, rounded and slightly elongated agglomerates ranging up
to approximately 1.60 mm in length. The fine elongated to round
particles that form the agglomerates range up to around 30.0
microns in length. Representative samples of AquaSolve MF and
MG HPMCAS are shown in Figures 3 and 4.
Figure 4 SEM imagery for AquaSolve MG HPMCAS; for all G

grades, particle size distribution is less than 1 mm
Figure 3 SEM imagery for AquaSolve MF HPMCAS; for all

F grades, D50 is near 5 m and D90 is near 10 m
Moisture Absorption
AquaSolve HPMCAS absorbs moisture from the air. The amount
absorbed and the rate of absorption depend on the initial moisture
content and on the relative humidity and temperature of the
surrounding air. Figure 5 shows the effect of relative humidity
on equilibrium moisture content of three grades of AquaSolve
HPMCAS.
Figure 5 Effect of relative humidity on equilibrium moisture
content of AquaSolve HPMCAS at 25C
Equilib
brium mo
oisture co
ontent (%
%)
10
A
AquaSolve
S l L HPMCAS
AquaSolve M HPMCAS
AquaSolve H HPMCAS
25
50
R l ti humidity
Relative
h idit (%)
75
100
Thermal Properties
Thermal Decomposition Temperature
Glass Transition Temperature

Glass transition temperatures (Tg) of polymers were tested using
differential scanning calorimetry (DSC) under a nitrogen purge
with a TA Instruments DSC2000 calorimeter on 5 mg samples. Each
sample was heated at a rate of 20C/minute from 20C to 190C
and then cooled at the same rate back to 20C. After cooling,
samples were held isothermal for 5 minutes and then heated again
at the same rate to 195C. The glass transition temperature was
identified as the half-height midpoint for the reheat data cycle. All
three grades of HPMCAS have a Tg near 120C (Figure 6 and Table
3). Glass transition temperature helps to guide the lower end of hotmelt extrusion processing temperature. Typically, hot-melt extrusion
is processed about 2040C above Tg.
Thermal decomposition temperature (Td) was measured by

thermogravimetric analysis (TGA). TGA was performed on 10 mg
samples in a TA Instruments TGA Q5000IR* thermogravimetric
analyzer under N2 atmosphere. Nitrogen flow rate was 25 ml/min at
normal air pressure with a heating rate of 10C/min. Samples were
heated to above 800C until 5% weight loss, excluding moisture
loss. All three grades of AquaSolve HPMCAS had decomposition
temperatures in the range of 258 to 276C (Figure 7 and Table 3).
Thermal decomposition temperature defines the higher end of the
extrusion temperature range.
Figure 7 Thermal decomposition temperatures for each grade of
AquaSolve HPMCAS
110
Figure 6 Glass transition temperatures for each grade of

AquaSolve HPMCAS
AquaSolve L HPMCAS
AquaSolve M HPMCAS
AquaSolve H HPMCAS
100
0.0
-0.2
Heat Flow (W/g)
Weight (%)
276C
AquaSolve L HPMCAS
AquaSolve M HPMCAS
AquaSolve H HPMCAS
119C
-0.4
258C
90
267C
80
120C
-0.6
70
122C
100
200
Temperature (C)
300
400
Universal V4.7A TA Instruments
-0.8
-1.0
Exo Up
50
100
150
Temperature (C)
200
Universal V4.7A TA Instruments
Table 3 Glass transition and thermal decomposition

temperatures of AquaSolve HPMCAS
L Grade
M Grade
H Grade
Tg
119
120
122
Td
258
267
276
Melt Viscosity
Melt viscosity information can help to identify the hot-melt
extrusion processing temperature window. The influence of shear
frequency (shear rate; see Figure 8) and temperature (see Figure
9) on melt viscosity were studied with a TA Instruments AR G2
stress-controlled rotational rheometer, with a 25 mm parallel-plate
geometry. The isothermal frequency sweep test was conducted
at 170C with a frequency range from 0.1 rad/s to 600 rad/s and a
strain in the linear viscoelastic region of the sample. All three grades
of AquaSolve HPMCAS show shear thinning behavior at 170C.
The temperature-sweep test was performed from 150C to 200C

with a heating rate of 2C/min. The measurement frequency was
set at 6.28 rad/s and the strain was within the linear viscoelastic
region of each sample. All grades of AquaSolve HPMCAS had
melt viscosities below 100,000 Pas at these temperatures,
which is the generally accepted upper viscosity limit for hot-melt
extrusion. Viscosities of all three grades decreased with increasing
temperature from 150C to 200C. The melt viscosity of the H grade
is significantly lower compared with the M and L grades, especially
at high temperatures.
Figure 8 Influence of shear frequency on melt viscosity of

AquaSolve HPMCAS at 170C
1,000,000
Viscos
sity (Pas)
100,000
10 000
10,000
Melt Viscosity with Various Plasticizers
AquaSolve L HPMCAS
1,000
AquaSolve M HPMCAS
q
AquaSolve
H HPMCAS
100
01
0.1
10
100
1000
Frequency (rad/s)
Figure 9 Melt viscosity of AquaSolve HPMCAS as a function of

temperature (measured at frequency of 6.28 rad/s)
Polymer and plasticizer mixtures were prepared by spray drying.

Melt viscosity was evaluated using the same conditions as for the
pure polymer. Results are shown in Figures 10 to 12 for each grade
of AquaSolve HPMCAS. All plasticizers effectively reduced the melt
viscosity to below 100,000 Pas, making extrusion possible at lower
temperatures (around 120C) to improve processability.
Figure 10 Melt viscosity of AquaSolve L HPMCAS with various
plasticizers at 10%
10,000,000
100,000
AquaSolve L HPMCAS
With dibutyl sebacate
With diethyl phthalate
Viscosity (Pas)
V
Viscos
sity (Pas)
1,000,000
10 000
10,000
AquaSolve L HPMCAS
A
AquaSolve
S l M HPMCAS
With polysorbate 80
With Vitamin E TPGS
100,000
1,000
150
160
170
180
Temperature (C)
With distilled acetylated

monoglycerides
10,000
AquaSolve H HPMCAS
1,000
With triethyl citrate
190
200
120
130
140
150
160
170
180
190
200
Temperature (C)
Figure 11 Melt viscosity of AquaSolve M HPMCAS with various

plasticizers at 10%
10,000,000
AquaSolve M HPMCAS
Viscosity (Pas)
1,000,000
With triethyl
y citrate
With polysorbate 80
With Vitamin E TPGS
100,000

monoglycerides
10,000
1,000
1 000
Viscosity in Various Solvents

A lower solution viscosity is advantageous for spray drying and
coating. The typical concentration of total solids for spray drying
is less than 10%, and concentrations of 3% to 5% are common.
For film coating, polymer concentration is generally less than 10%
in solution. The viscosity of solutions of each grade of AquaSolve
HPMCAS in various solvents was measured using a Brookfield
viscometer. Results are shown in Figures 13 through 15. At 10%
solids content, a viscosity less than 300 mPas indicates good
processability.
Figure 13 Viscosity of AquaSolve L HPMCAS at 20C in various
solvents
120
130
140
150
160
170
180
190
200
10000
Acetone
Temperature (C)
2:1 Ethanol:Acetone
8:2 Ethanol:Water
Methanol
Figure 12 Melt viscosity of AquaSolve H HPMCAS with various

plasticizers at 10%
10,000,000
Visc
cosity (mPas)
1000
2:1 Methylene chloride: Methanol
100
10
AquaSolve H HPMCAS
1,000,000
With triethyl
y citrate
V
Viscosity
y (Pas)
With polysorbate 80
100 000
100,000
10
15
HPMCAS concentration (%)
Figure 14 Viscosity of AquaSolve M HPMCAS at 20C in various

solvents
1000
120
130
140
150
160
170
Temperature (C)
180
190
Acetone
2:1 Ethanol:Acetone
200
8:2 Ethanol:Water
Methanol
Visc
cosity (mPas)
1,000
,
20

monoglycerides
10,000
100
2:1 Methylene chloride:

Methanol
10
10
With Vitamin E TPGS
10
15
20
Figure 15 Viscosity of AquaSolve H HPMCAS at 20C in various

solvents
Figure 16 Disintegration time of films made from various grades

of AquaSolve HPMCAS
120
1000
Acetone
100
Disiintegration time (min)
2:1 Ethanol:Acetone
8:2 Ethanol:Water
Vis
scosity (mPas)
Methanol
100
2:1 Methylene chloride:

Methanol
10
AquaSolve L
HPMCAS
AquaSolve M
HPMCAS
AquaSolve H
HPMCAS
80
60
40
20
0
0
10
15
20
5.5
6.5
7.5
pH of USP phosphate buffer
Solubility at Various pH
Film Strength
Polymer solubility at various pH was evaluated by disintegration of

films in phosphate buffer solutions. Films were cast with acetone
as the solvent to a thickness of 90 m and cut into squares of 1.3
cm. Disintegration time was measured using a USP disintegration
apparatus at 37C following general USP disintegration guidelines.
Results varied by grade and pH, as shown in Figure 16.
The films prepared for the dissolution testing were also used for
film tensile strength evaluations. Films were cast to a thickness of
90 m. An Instron Universal Tensile tester was used to perform the
evaluations. Results are described in Table 4. Aquasolve L, M, and H
grades of HPMCAS have similar film characteristics.
Table 4 Film strength results
Grade of AquaSolve
and AquaSolve AS
HPMCAS
Elongation
(%)
Modulus
(MPa)
Yield Stress
(MPa)
11
1574
35
19
1523
37
16
1494
40
11
Applications
Solid Dispersion for Bioavailability Enhancement

Acetyl and succinoyl substitution levels have a significant impact
on the performance of HPMCAS as an amorphous solid-dispersion
carrier. This effect is demonstrated in a case study in which the
dissolution performance of solid dispersions prepared by spray
drying using AquaSolve HPMCAS L, M and H grades and the
poorly soluble compounds ezetimibe (EZE), itraconazole (ITZ) and
felodipine (FEL) was evaluated. The acetyl to succinoyl ratios of the
AquaSolve L, M and H HPMCAS grades were 0.48, 0.87 and 1.8,
respectively.
Spray-drying solutions were prepared by dissolving model
compound and polymer into 2:1 (w/w) dichloromethane:methanol
solution at 5% solids. Spray drying was performed on a GEA SD
Micro* Spray-Dryer. The feed material was atomized using a 0.5 mm
two-fluid Schlick nozzle targeting an inlet temperature of 85C, a
process gas flow of 25 kg/hr, an atomizing gas pressure of 0.5 bar,
and an atomizing-gas flow rate of 1.5 kg/hr. The liquid-feed rate
was adjusted to maintain an outlet gas temperature of 55C. After
spray drying, the spray-dried dispersions were vacuum dried for 48
hours at 40C under 25 in. Hg reduced pressure.
The spray-dried powders were evaluated for the amorphous
characteristics of the samples and the dissolution performance. All
spray-dried solid dispersions were characterized as amorphous by
X-ray powder diffraction (XRPD) performed on a Bruker D8 Focus
diffractometer, using a copper tube element and a PSD LynxEye*
detector.
12
Dissolution experiments were performed using a Pion DISS

Profiler* dissolution apparatus. Spray-dried samples were added to
20 ml of fasted-state simulated intestinal fluid (FaSSIF) maintained
at 37C under a constant stirring speed of 300 rpm. A 2.0 mg model
drug equivalent of each spray-dried powder was added to each vial
and drug concentration was measured by in situ fiber optic probes
at various time points.
For the solid dispersions of all three model compounds, L grades
consistently gave the fastest initial dissolution (Figures 17 through
19). The ability of the polymer to maintain supersaturation was
highly dependent on the interaction between model drug and
polymer.
Figures 17 through 19 show the relative performance of AquaSolve
HPMCAS with different substitution levels on solubilization
enhancement of model drugs with varying solubility.
Figure 17 Kinetic solubility results for spray-dried dispersions
produced with itraconazole (ITZ) and each grade of AquaSolve
HPMCAS at 25% drug load
180
160
140
Concentratiion (g/m
ml)
HPMCAS has been used as an enteric film-coating polymer for

tablets and also for capsules. Its effectiveness as a solid-dispersion
carrier for bioavailability enhancement has attracted the most
attention in recent years. Numerous publications have indicated
that HPMCAS is able to initiate and maintain supersaturation for
drugs with a wide variety of structures and physical properties, and
the efficacy advantage of HPMCAS is primarily due to the polymers
superiority as a precipitation inhibitor via the formation of colloidal
species in aqueous media.1,2
120
25% Itraconazole AquaSolve L HPMCAS
100
25% Itraconazole AquaSolve M HPMCAS

25% Itraconazole AquaSolve H HPMCAS
80
Itraconazole API
60
40
20
0
Solubility of
itraconazole: < 1 mg/l
50
100
Time (minutes)
150
200

produced with ezetimibe (EZE) and each grade of AquaSolve
120
50% Ezetimibe and AquaSolve
L HPMCAS
q
100
50% Ezetimibe and AquaSolve M HPMCAS
Con
ncentratio
on (g/ml)
50% Ezetimibe and AquaSolve H HPMCAS

Ezetimibe API
80
60
40
Solubility of
ezetimibe: 8.46 mg/l
20
0
50
100
Time (minutes)
150
200

produced with felodipine (FEL) and each grade of AquaSolve
600
Concentratio
on (g/mll)
40% Felodipine and AquaSolve L HPMCAS

40% Felodipine and AquaSolve M HPMCAS
40% Felodipine and AquaSolve H HPMCAS
Felodipine API
300
200
100
0
Solubility of
felodipine: 19.7 mg/l
50
100
Time (minutes)
It can be concluded from this case study that for basic compounds,
like itraconazole, the L grade with more succinoyl groups can
form ionic interactions and result in solid dispersions with better
dissolution performance. For hydrophobic compounds such as
ezetimibe and felodipine that are non-ionizable or acidic, the more
hydrophobic H and M grades offer better performance due to their
strong interactions with the compounds. In addition, the dissolution
rate of the polymers has significant impact on the dissolution rate
of the solid dispersions.
Enteric Coating
500
400
As indicated in Figure 17, the itraconazole solid dispersion had a

greater area under the dissolution curve (AUC) when formulated
with AquaSolve L and M grades of HPMCAS. Itraconazole is a
weakly basic compound that can form ionic interactions with the
succinoyl groups of HPMCAS. The L and M grades have more readily
available succinoyl groups and rendered solid dispersions with
better dissolution performance. Both ezetimibe (weak acid) and
felodipine (neutral) showed low AUCs with L grade solid dispersions
and higher AUC in M- and H-grade solid dispersions (Figures 18 and
19). For both compounds, M-grade solid dispersions performed
similarly with H-grade solid dispersions. AquaSolve M and H
HPMCAS are more hydrophobic than L grade, as indicated by their
higher acetyl to succinoyl ratios, and these two grades therefore
have stronger intermolecular interactions with hydrophobic
ezetimibe and felodipine and were able to maintain supersaturation
for prolonged periods.
150
200
This case study was performed on tablets containing omeprazole

as the model drug. Omeprazole is a proton-pump inhibitor that is
unstable in acidic conditions, making an enteric coating necessary.
An enteric coating dispersion formulation was prepared using
a neutralization method by adding basic agents. The coating
formulations are listed in Table 5 and were prepared as follows:
triethyl citrate and sodium lauryl sulfate were added to water (at
ambient conditions) and stirred for 5 min. AquaSolve HPMCAS
and talc were added and stirred until uniformly distributed. Finally,
monoethanolamine was added to the dispersion, pH was adjusted
to pH 8 (target pH 79) with ammonium hydroxide and the
mixture was stirred for 3 h at ambient conditions until no HPMCAS
particles were left. The final step was filtration with a 20 mesh sieve.
Alternatively, a 20 mesh screen can be placed at the end of the inlet
tubing. The dispersion was gently stirred during the entire coating
process to prevent the precipitation of talc.
13
Table 5 Omeprazole tablet coating formulations

Percent by Weight
HPMCAS (L, M or H)
58.1
Monoethanolamine
3.4
Triethyl citrate
14.8
Sodium lauryl sulfate
1.6
Talc
20.0
Ammonium hydroxide
~2.1
100
The formulations were coated on 300 mg tablets containing a 20

mg dose of omeprazole, using the parameters listed in Table 6.
Ome
eprazole released
d (%)
Ingredient
Figure 20 Dissolution testing results for AquaSolve L HPMCAS

under the U.S. Pharmacopoeia testing methods
40
pH 6.8
pH 1.2
OHara LabCoat II
Pan size
AquaSolve L HPMCAS
60
20
Table 6 Omeprazole tablet coating parameters

Parameter
80
30
90
120
150
Time (min)
15 inch
Gun
Schlick 1.2 mm
Pan load (kg)
Pan speed (rpm)
14
Bed temperature (C)
Figure 21 Dissolution testing results for AquaSolve M and H

HPMCAS under the British Pharmacopoeia testing methods
4550
20
Inlet temperature (C)
5560
Outlet temperature (C)
4345
Air volume (cfm)
175
Atomizing air pressure (psi)
30
Pattern air pressure (psi)
30
100
Final solution viscosity of the coating was 100 to 300 mPas with a
solids content of 15%. Tablets were coated to a 20% weight gain.
Omeprazole dissolution analysis with high-performance liquid
chromatography (HPLC) was made to ensure compliance with the
British and U.S. pharmacopoeia standards for drug release, detailed
in Table 7. The L grade of AquaSolve HPMCAS was tested using the
U.S. Pharmacopoeia (USP) method <711>. The M and H grades were
tested using the British Pharmacopoeia (BP) monograph for gastroresistant omeprazole tablets. Results of the dissolution testing are
shown in Figures 20 and 21.
Omeprazole re
eleased (%
%)
Spray rate (g/min)
80
AquaSolve M HPMCAS
60
AquaSolve H HPMCAS
40
pH 6.8
20
pH 4.5
p
Table 7 Omeprazole tablet release criteria

BP Method
14
60
USP Method
pH 4.5
pH 6.8
pH 1.2
pH 6.8
45 min
45 min
2 hr
30 min
< 10%
> 60%
< 10%
> 75%
15
30
45
Time (min)
60
75
90
Incompatibilities
References
Stability and Storage Conditions
2. Curatolo, W., J. A. Nightingale and S. M. Herbig. Utility of Hydroxypropylmethylcellulose

Acetate Succinate (HPMCAS) for Initiation and Maintenance of Drug Supersaturation in
the GI Milieu. Pharmaceutical Research. 26 (2009): 14191431.
3. Hoshi, N., K. Ueno, H. Yano, K. Hirashima & H. Kitagawa. General Pharmacological
Studies of Hydroxypropylmethylcellulose Acetate Succinate in Experimental Animals.
Journal of Toxicological Sciences. 10(Suppl 2). (1985): 129146.
AquaSolve HPMCAS is incompatible with strong acids or bases,

oxidizing agents and sustained levels of elevated humidity.
AquaSolve HPMCAS should be stored in a well-closed container,

in a cool, dry place. In such storage conditions, HPMCAS is a stable
material. HPMCAS is hygroscopic and can hydrolyze to acetic acid
and succinic acid over prolonged periods of time. Hydrolysis is
the main degradation pathway that is responsible for increasing
amounts of free acids in storage, especially upon exposure to
moisture.
Packaging and Shipping
The moisture content of AquaSolve HPMCAS does not exceed

5% by weight when the products are packed. Because of varying
storage and shipping conditions, there is a possibility of some
moisture pickup from the as-packed value. Although packaging
has been designed to reduce moisture pick up, product should
be stored under clean, dry conditions and used in rotation.
The standard product packaging is 25 kg net weight sealed
polyethylene bags, shipped in drums. The type, lot number and
drum number are stenciled on the outside of each drum. Read and
understand the Safety Data Sheet (SDS) before using this product.
Regulatory Status
1. Friesen, D. T., R. Shanker, M. Crew, D. T. Smithey, W. J. Curatolo, and J. A. S. Nightingale.

Hydroxypropyl Methylcellulose Acetate Succinate-based Spray-dried Dispersions: An
Overview. Molecular Pharmaceutics. 5 (2008): 10031019.
4. Hoshi, N., H. Yano, K. Hirashima, H. Kitagawa & Y. Fukuda. Toxicological Studies of

Hydroxypropylmethylcellulose Acetate SuccinateAcute Toxicity in Rats and Rabbits,
and Subchronic and Chronic Toxicities in Rats. Journal of Toxicological Sciences.
10(Suppl 2). (1985): 147185.
5. Hoshi, N., K. Ueno, T. Igarashi, H. Kitagawa, T. Fujita, N. Ichikawa, Y. Kondo & M. Isoda.
Teratological Studies of Hydroxypropylmethylcellulose Acetate Succinate in Rats.
6. Cappon, G. D., T. L. Fleeman, M. S. Rocca, J. C. Cook & M. E. Hurtt. Embryo/Fetal
Development Studies with Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS)
in Rats and Rabbits. Birth Defects Research Part B: Developmental and Reproductive
Technology. 68. (2003): 421427.
Teratological Study of Hydroxypropylmethylcellulose Acetate Succinate in Rabbits.
Studies of Hydroxypropylmethylcellulose Acetate Succinate on Fertility in Rats. Journal
of Toxicological Sciences. 10(Suppl 2). (1985): 187201.
Effects on Offspring Induced by Oral Administration of Hydroxypropylmethylcellulose
Acetate Succinate to the Female Rats in Peri- and Post-natal Periods. Journal of
Toxicological Sciences. 10(Suppl 2). (1985): 235255.
All AquaSolve HPMCAS grades conform to the monograph

requirements of the current editions of the National Formulary
and Japanese Pharmacopoeia. Please contact your Ashland
representative for access to the Excipient Information Package (EIP)
for further details.
Toxicology
AquaSolve hypromellose acetate succinate (HPMCAS) is insoluble

in water and this, combined with a molecular weight range
between 10,000 and 500,000 daltons, indicates that it is not orally
bioavailable. There were no adverse effects in several toxicological
studies, including chronic or reproductive and developmental
animal studies.39 HPMCAS is an approved pharmaceutical excipient
for oral dosage forms. The present Inactive Ingredient Database
limit for HPMCAS is 560 mg per day.
15
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Tel: +1 859 815 3333
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Tel: +1 877 546 2782
Regional Centers
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Tel: +41 52 560 55 00
Fax: +41 52 560 55 99
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Tel.: +65 6775 5366
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Tel.: +5255 5211 0111
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pharmaceutical@ashland.com
ashland.com/aquasolve
Registered trademark, Ashland or its subsidiaries, registered in various countries
Trademark, Ashland or its subsidiaries, registered in various countries
2013, 2014, Ashland
PC-12624.1
All statements, information and data presented herein are

believed to be accurate and reliable, but are not to be taken
as a guarantee, an express warranty, or an implied warranty
of merchantability or fitness for a particular purpose, or
representation, express or implied, for which Ashland Inc.
and its subsidiaries assume legal responsibility.

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AquaSolve and

hydroxypropylmethylcellulose acetate succinate

Physical and chemical properties

With good chemistry great things happen.

AquaSolve and AquaSolve AS Hydroxypropylmethylcellulose Acetate Succinate

AquaSolve (AquaSolve AS in the United Kingdom)

AquaSolve HPMCAS has the following functions and properties:

AquaSolve HPMCAS can be used as a solid-dispersion carrier for

It is an enteric coating polymer.

It is practically insoluble in water, ethanol and hexane.

These properties and functions make it suitable for use in many

AquaSolve and AquaSolve AS Hydroxypropylmethylcellulose Acetate Succinate

Figure 1 shows the structure of the HPMCAS molecule; it is

CAS Name: Cellulose, 2-hydroxypropyl methyl ether, acetate

Grades and Types

Table 1 AquaSolve HPMCAS grades

AquaSolve and AquaSolve AS Hydroxypropylmethylcellulose Acetate Succinate

Figure 2 shows the available grades of AquaSolve HPMCAS plotted

Figure 2 Available grades of AquaSolve HPMCAS

Table 2 Product specifications

Detailed product specifications are listed in Table 2.

Conforms to U.S. National Formulary and

Acetyl Content (wt%)

Average Particle Size

Measured for a 2% solution at 20C.

Ashland can tailor certain chemical and physical properties of

Limit of Free Succinic

White to off-white powder (F) or granules (G)

AquaSolve and AquaSolve AS Hydroxypropylmethylcellulose Acetate Succinate

Figure 4 SEM imagery for AquaSolve MG HPMCAS; for all G

Figure 3 SEM imagery for AquaSolve MF HPMCAS; for all

AquaSolve and AquaSolve AS Hydroxypropylmethylcellulose Acetate Succinate

Thermal Decomposition Temperature

Glass Transition Temperature

Thermal decomposition temperature (Td) was measured by

Figure 6 Glass transition temperatures for each grade of

Heat Flow (W/g)

Universal V4.7A TA Instruments

Universal V4.7A TA Instruments

Table 3 Glass transition and thermal decomposition

AquaSolve and AquaSolve AS Hydroxypropylmethylcellulose Acetate Succinate

The temperature-sweep test was performed from 150C to 200C

Figure 8 Influence of shear frequency on melt viscosity of

Melt Viscosity with Various Plasticizers

Figure 9 Melt viscosity of AquaSolve HPMCAS as a function of

Polymer and plasticizer mixtures were prepared by spray drying.

With distilled acetylated

With triethyl citrate

AquaSolve and AquaSolve AS Hydroxypropylmethylcellulose Acetate Succinate

Figure 11 Melt viscosity of AquaSolve M HPMCAS with various

With distilled acetylated

Viscosity in Various Solvents

Figure 12 Melt viscosity of AquaSolve H HPMCAS with various

2:1 Methylene chloride: Methanol

Figure 14 Viscosity of AquaSolve M HPMCAS at 20C in various

With distilled acetylated

2:1 Methylene chloride:

With Vitamin E TPGS

AquaSolve and AquaSolve AS Hydroxypropylmethylcellulose Acetate Succinate

Figure 15 Viscosity of AquaSolve H HPMCAS at 20C in various

Figure 16 Disintegration time of films made from various grades

2:1 Methylene chloride:

pH of USP phosphate buffer