Food & Pharma Solutions
AFFINISOL™ HPMCAS for Spray-Dried Dispersion (SDD)
Solving the Insoluble with Dow
Dow Pharma & Food Solutions
At Dow Pharma & Food Solutions, we appreciate that
solubilization of a pipeline of poorly soluble drug candidates
is the leading challenge facing the pharmaceutical industry.
Thus, we designed AFFINISOL™, our solubilization polymer
portfolio, to help you solve the insoluble. Our AFFINISOL™
polymers are uniquely tailored to address the solubilization
performance requirements of your APIs, whether you have
chosen to formulate via Spray-Dried Dispersion (SDD) or Hot
Melt Extrusion (HME).
AFFINISOL™ Hypromellose Acetate Succinate (HPMCAS) is
an excellent polymer for the formation of solid dispersions
with active pharmaceutical ingredients (APIs). HPMCAS is a
soluble polymer that can help maintain stable solid dispersions
and inhibit API crystallization in solution promoting
supersaturation of the drug. In addition, AFFINISOL™ HPMCAS
offers flexibility in acetate and succinate substitution levels
helping for optimization of both solubility enhancement
and material processing. These combined properties make
AFFINISOL™ HPMCAS an excellent choice for formulating BCS
Class II and Class IV compounds.
Through its leadership in investments in infrastructure and
R&D capabilities, Dow helps provide proven and innovative
polymers for solubility enhancement. Dow combines a deep
understanding of critical polymer properties with small scale
synthesis capability to partner with your development team
and offer an excellent product that is scientifically designed
to address your API’s unique needs. AFFINISOL™ HPMCAS goes
beyond the products commercially available today, offering
more options to help maximize solubilization performance.
Via Spray-Dried Dispersion
(SDD)
AFFINISOLTM HPMCAS
716, 912, 126 HPMCAS
QbD design over full USP
Monograph
Solubility Enhancement
Platform
AFFINISOLTM HPMCAS HP
(High Productivity)
facilitating higher thoughput
in spray-drying
Via Hot Melt Extrusion
(HME)
AFFINISOLTM HPMC HME
new grade of HPMC with improved
thermal properties
2
AFFINISOL™
Hyrdroxypropyl Methylcellulose Acetate
Succinate (HPMCAS)
Dow has created AFFINISOL™ HPMCAS, building on over half
a century of cellulosic expertise. AFFINISOL™ HPMCAS is
hydroxypropyl methylcellulose (HPMC) functionalized with
a mixture of monosuccinic acid and acetic acid esters (Figure
1). AFFINISOL™ HPMCAS has been developed to create stable
amorphous solid dispersions (ASDs) with poorly soluble active
pharmaceutical ingredients (APIs). The ability of AFFINISOL™
HPMCAS to form stable ASDs can result in solubility
enhancement and a subsequent increase in bioavailability.
Figure 1. The reaction scheme to convert HPMC to HPMCAS.
AFFINISOL HPMCAS
AFFINSIOL™ HPMCAS is available in three standard commercial
cGMP granular grades: HPMCAS 716, HPMCAS 912, and HPMCAS
126 (Figure 2). These three grades are differentiated by the ratio
of succinyl and acetyl substituents on the HPMC backbone
(Table 1). AFFINISOL™ HPMCAS meets the requirements of the
United States Pharmacopeia National Formulary (USP-NF) and
the Japanese Pharmaceutical Excipients (JPE), depicted by the
region in Figure 2. AFFINISOL™ HPMCAS is a white to off-white
powder with a faint acetic acid odor.
Succinyl (wt %)
™
30
28
26
24
22
20
18
16
14
12
10
8
6
4
2
0
UPS-NF and JPE Range
HPMCAS 716
HPMCAS 912
HPMCAS 126
0
2
4
6
8
10
12
14
16
18
Acetyl (wt %)
Figure 2. The USP-NF monograph substitution space for HPMCAS and
the standard AFFINISOL™ HPMCAS 716, HPMCAS 912 and HPMCAS 126
substitution ranges.
Table 1. Specifications of AFFINISOL HPMCAS
AFFINISOL™ HPMCAS
716
912
126
5.0 – 9.0 %
5.0 – 9.0 %
6.0 – 10.0 %
Methoxyl
20.0 – 24.0 %
21.0 -25.0 %
22.0 – 26.0 %
Viscosity*
2.4 – 3.6 cP
2.4 – 3.6 cP
2.4 – 3.6 cP
< 0.20 %
< 0.20 %
< 0.20 %
Hydroxypropyl
Residue on Ignition
Loss on Drying
< 5.0 %
< 5.0 %
< 5.0 %
Free Acids
< 1.0 %
< 1.0 %
< 1.0 %
5.0-9.0 %
7.0 – 11.0 %
10.0 – 14.0 %
14.0-18.0 %
10.0 – 14.0 %
4.0 – 8.0 %
0.5 %
0.5 %
0.5 %
Acetate Substitution
Succinate Substitution
Acetic Acid
* Viscosity determined as a 2 % solution in NaOH solution
3
Dow Pharma & Food Solutions
Table 2. Solubility of AFFINISOL™ HPMCAS in Solvents Typically Used for Spray Drying
The physical properties of AFFINISOL™
HPMCAS make it a desirable excipient
for spray drying with poorly water
soluble APIs. AFFINISOL™ HPMCAS
is soluble in a wide range of organic
solvents (Table 2) which makes it
compatible with a range of APIs.
Additionally, AFFINISOL™ HPMCAS
has a pH dependent solubility in aqueous
media, allowing for targeted delivery
of an active. The Hansen Solubility
Parameters have been determined
for each grade to aid in determining
compatibility with an API (Table 3).
Solvent
HPMCAS 716
HPMCAS 912
HPMCAS 126
DI – Water
I
I
I
Methanol
S
S
S
Methanol/Dichloromethane (1:2)
S
S
S
Ethanol
I
I
P
Ethanol/Water (4:1)
S
S
S
Ethanol/Dichloromethane (1:1)
S
S
S
Acetone
S
S
S
Tetrahydrofuran
S
S
S
Methylene Chloride
S
S
S
S = Soluble; P = Partially Soluble; I = Insoluble
Table 3. Hansen Solubility Parameters for AFFINISOL™ HPMCAS
Interaction Radius
(J/cc)0.5
Polar
(J/cc)0.5
Hydrogen Bonding
(J/cc)0.5
Dispersive
(J/cc)0.5
HPMCAS 716
10.06
11.87
10.19
17.77
HPMCAS 912
10.76
12.37
10.33
16.73
HPMCAS 126
9.85
12.76
9.67
18.09
AFFINISOL™ HPMCAS viscosity is dependent on the concentration and solvent system used. This is demonstrated in Figure 3A in
which the rheology of all three grades of AFFINISOL™ HPMCAS are shown as 20 wt% solutions in acetone. Additionally, Figure 3B
shows the rheology of AFFINISOL™ HPMCAS 716 compared at several polymer concentrations in two separate solvent systems. The
viscosity of a solution for spray-drying is a critical factor in achieving an ideal formulation. The ability of AFFINISOL™ HPMCAS to
be dissolved in multiple organic solvents and solvent systems allows flexibility in production of a spray-dried dispersion.
A.
B.
700
10,000
1,000
500
viscosity [mPas]
vicosity [mPas]
600
400
300
200
100
10
100
0
0.1
1
1
10
100
0.1
1
shearrate [1/s]
AFFINISOL™ HPMCAS 126
AFFINISOL™ HPMCAS 912
AFFINISOL™ HPMCAS 716
10% Acetone
10% in DCM/Ethanol 1:1
10
shearrate [1/s]
15%Acetone
15% in DCM/Ethanol 1:1
100
1,000
20% Acetone
20% in DCM/Ethanol 1:1
Figure 3. A. Rheology of AFFINISOL™ HPMCAS 716, 912, and 126 as a 20 wt % solution in acetone at 20 °C. B. Rheology of AFFINISOL™ HPMCAS 716 as 10 wt %, 15 wt %
and 20 wt % solutions in acetone and a 1:1 dichloromethane (DCM) – ethanol solvent mixture at 20 °C.
4
AFFINISOL™
AFFINISOL™ HPMCAS absorbs moisture from the air. The
amount of moisture absorbed depends on several factors
including the starting moisture level, temperature and
substitution levels of the polymer. The moisture sorption of
AFFINISOL™ HPMCAS is demonstrated in Figure 4.
Water Sorption (% by mass)
Moisture Absorption
11
10
9
8
7
6
5
4
3
2
1
0
0
10
20
30
40
50
60
70
80
90
100
Relative Humidity (%)
HPMCAS 716 G LOT 2I1150ND6A
HPMCAS 912 G LOT 2I10950ND6A
HMPCAS 126 G Lot 2I1050ND6A
Figure 4. Moisture sorption of AFFINISOL™ HPMCAS as a function of
relative humidity
100
Thermal Properties
Weight Percent
99
98
97
96
95
94
93
92
25
50
75
100
AFFINISOL™ HPMCAS 716
125 150 175
Temperature (°C)
AFFINISOL™ HPMCAS 912
200
225
250
AFFINISOL™ HPMCAS 126
Figure 5. Thermal gravimetric analysis of AFFFINISOL HPMCAS
Glass Transition Temperature (°C)
AFFINISOL™ HPMCAS is a robust polymer with a degradation
onset temperature near 200°C (Figure 5) providing a
broad processing window for API formulation. In addition,
AFFINISOL™ HPMCAS has a high glass transition temperature
(Tg) to provide excellent stability to amorphous solid
dispersions of an API in the polymer. As demonstrated in
Figure 6, the Tg of AFFINISOL™ HPMCAS varies with the
acetate and succinate substitution levels as well as with
absorbed moisture content.
140
120
100
80
60
40
20
0
0
10
20
30
40
50
60
70
80
90
100
Relative Humidity (%)
AFFINISOL™ 716
AFFINISOL™ 912
AFFINISOL™ 126
Figure 6. The Tg of AFFINISOL™ HPMCAS as a function of relative humidity.
5
Dow Pharma & Food Solutions
AFFINISOL™ HPMCAS for Spray-Dried
Dispersion (SDD)
HPMCAS has demonstrated utility in forming amorphous solid
dispersions with poorly soluble APIs that result in an apparent
solubility enhancement through its ability to achieve and
sustain a supersaturated solution of the API.[1, 2] In addition,
the formation of an amorphous solid dispersion with HPMCAS
has been shown to have little or no impact on the permeability
of the API.[3] The extent of solubility enhancement and
sustainment is dependent on acetate and succinate content of
the polymer, and the optimum ratio varies for each API. This is
demonstrated in Figure 8 where the solubility of phenytoin and
itraconazole amorphous solid dispersions with all AFFINISOL™
HPMCAS grades were evaluated.
The SDDs were created by dissolving phenytoin in acetone or
itraconazole in tetrahydrofuran and adding the AFFINISOL™
Drug release from the isolated powder was evaluated by
transferring 7.2 mg of the SDD into a microcentrifuge tube. The
powder was diluted with 1.8 mL fasted simulated intestinal fluid
at pH 6.5. At each sample time, the samples were centrifuged
for 1 min at 13,000 x g. Fifty microliters of the supernate was
removed and diluted with 250 µL of MeOH. The amount of
dissolved drug was detected by HPLC-UV. All sample preparation
steps were completed in a 37°C constant temperature box.[1]
B.
1000
1000
900
900
800
800
Concentration (µg/ml)
Concentration (µg/ml)
A.
HPMCAS to the solution to give a clear to slightly opaque
final solution with 25 wt% API to 75 wt% AFFINISOL™ HPMCAS
ratio. The solutions were spray dried on a Bend miniSD spray
drying unit and the resulting samples were dried at 25 °C under
reduced pressure. The dispersions were analyzed by DSC and
PXRD to confirm amorphous dispersions were created.
700
600
500
400
300
200
700
600
500
400
300
200
100
100
0
0
0
50
100
150
200
250
300
350
400
0
50
100
Time (Minutes)
AFFINISOL HPMCAS 716
AFFINISOL HPMCAS 912
150
200
250
300
350
Time (Minutes)
AFFINISOL HPMCAS 126
AFFINISOL HPMCAS 716
AFFINISOL HPMCAS 912
AFFINISOL HPMCAS 126
Figure 7. Dissolution profiles for 25 wt % amorphous solid dispersions formed with (A.) phenytoin and (B.) itraconazole in AFFINISOL HPMCAS demonstrating the solubility
enhancement dependence on acetate and succinate substitution levels.
6
400
AFFINISOL™
Quality by Design (QbD) Formulation with
AFFINISOL™ HPMCAS
With a complete understanding of the synthetically viable
acetate and succinate substitution levels and the levels that
provide good organic solubility, the ideal polymer substitution
range can be identified. Dow’s Six Sigma Black Belts used
Design of Experiment (DoE) principals to create a partial
factorial sample set with linear constraints for the acetate and
succinate substitution range (Figure 9). This sample set also
includes samples of the standard AFFINISOL™ HPMCAS grades
to provide a complete study of formulation robustness with
HPMCAS. Utilizing this sample set provides a Quality by Design
(QbD) approach to formulation to faciliate the most robust drug
product possible.
35
30
% Succinyl
25
Degree of Substitution >3
20
15
10
5
0
0
2
USP-NF Range
4
6
HPMCAS 716
8
10
% Acetyl
HPMCAS 912
12
14
HPMCAS 126
16
18
HPMCAS Samples
Figure 8. Demonstration of a high throughput synthesis exploration of the
acetate and succinate substitution space. For cellulosic polymers a degree of
substitution greater than 3 is not possible.
30
25
Degree of Substitution >3
% Succinyl
The solubility enhancement performance of amorphous solid
dispersions formed with HPMCAS has a strong dependence on the
acetate and succinate substitution levels. AFFINISOL™ HPMCAS
716, HPMCAS 912, and HPMCAS 126 represent only a small
portion of the substitution space that is approved for use by the
USP-NF and the JPE. A formulation with HPMCAS 716, 912, and
126 may provide enhanced solubility, however that formulation
may not be robust to lot to lot variation in acetate and succinate
substitution. Dow Pharma and Food Solutions has the capability to
perform high throughput synthesis of HPMCAS polymers allowing
the complete exploration of the acetate and succinate space.
Figure 8 demonstrates a set of high throughput experiments to
explore the acetate and succinate substitution space. In addition
Dow has high throughput screening techniques to rapidly test
polymers with APIs to identify good excipient candidates.
20
15
10
Poor Solubility
5
0
0
USP-NF Range
2
4
HPMCAS 716
6
8
10
% Acetyl
HPMCAS 912
12
HPMCAS 126
14
16
18
HPMCAS QbD Samples
Figure 9. DoE sample set of AFFINISOL™ HPMCAS with AFFINISOL™ HPMCAS
716 (maroon), AFFINISOL™ HPMCAS 912 (orange) and AFFINISOL™ HPMCAS 126
(yellow) included. This sample set provides a QbD approach to understanding the
robustness of a formulation.
7
Dow Pharma & Food Solutions
Model API
T (°C)
T (°C)
clogP
286
2.2
166
7.1
Griseofulvin
89
220
2
Danazol
88
225
4.1
Succinyl, weight (%)
71
60
Succinyl, weight (%)
Phenytoin
Itraconazole
Acetyl, wt %
Acetyl, wt %
ITZ AUC90
GRIS AUC90
≤8200
≤4.37e+4
≤1.4e+4
≤2.6e+4
≤1.53e+4
≤5.08e+4
≤1.7e+4
≤2.9e+4
≤2.24e+4
≤5.79e+4
≤2e+4
≤3.2e+4
≤2.95e+4
≤6.5e+4
≤2.3e+4
≤3.5e+4
≤3.66e+4
Succinyl, weight (%)
AFFINISOL™ HPMCAS QbD sample sets can
be customized to your formulation need and
are available from our lab and cGMP Market
Development Plant. Identifying the best HPMCAS
composition for robust drug performance and being
able to support scale-up to commercialization are
key differentiators of the Dow custom and QbD
offering for AFFINISOL™ HPMCAS.
Table 4. Model compounds and physical properties of APIs used with AFFINISOL™ HPMCAS QbD
sample set.
Succinyl, weight (%)
To demonstrate the need for QbD studies of the
acetate and succinate substitution levels, four model
poorly soluble APIs, itraconazole, griseofulvin,
danazol, and phenytoin, with a range of physical
properties were studied (Table 4) with the DoE
sample set. Spray dried dispersions and solubility
studies were performed as described previously.
Performance maps for the solubility enhancement
capability of each HPMCAS polymer in the set
were created using the area under the curve
(AUC) to the 90 minute time point (Figure 10).[4]
These model studies demonstrate how each API is
unique and requires in-depth study to formulate
with HPMCAS. For example, itraconazole forms
a robust formulation with HPMCAS polymers
having between 5 and 10 weight percent acetate
and 10 to 18 weight percent succinate. In contrast,
griseofulvin displays the maximum solubility
enhancement with the AFFINSIOL™ HPMCAS 126
grade. However, as the acetate and succinate levels
change only slightly, the solubility enhancement
performance rapidly decreases.
Acetyl, wt %
DAN AUC90
Acetyl, wt %
PHY AUC90
≤5500
≤1.15e+4
≤1.3125e+4
≤2.5625e+4
≤7000
≤1.3e+4
≤1.625e+4
≤2.875e+4
≤8500
≤1.45e+4
≤1.9375e+4
≤3.1875e+4
≤10000
≤1.6e+4
≤2.25e+4
≤3.5e+4
Figure 10. Performance maps (red is highest solubility; blue is lowest solubility) with the
AFFINISOL™ HPMCAS QbD sample set with model compounds Itraconazole, Griseofulvin,
Danazol, and Phenytoin.[4] The performance maps demonstrate the need to have a full
understanding of the allowable HPMCAS substitution space and how minor changes in acetate
and succinate substitution can have a substantial impact on solubility enhancement.
8
AFFINISOL™
Next Generation AFFINISOL™ HPMCAS
AFFINISOL™ High Productivity HPMCAS
100
To further improve on the utility of AFFINISOL HPMCAS for
spray-dried dispersion Dow has developed the next generation
AFFINISOL™ HPMCAS.
™
Viscosity @ 100s-1
80
AFFINISOL™ High Productivity HPMCAS has been developed
to give the same solubility enhancement performance of
AFFINISOL™ HPMCAS while helping to improve the spray drying
solution throughput during manufacturing. By creating a lower
viscosity HPMCAS, Figure 11, the solids loading in the solvent can
be increased to provide higher solids throughput in the spray
drying process in the same unit time and reduce the amount of
organic solvent used. AFFINISOL™ High Productivity HPMCAS
can increase spray drying throughput by as much as 1.7x over
conventional HPMCAS, resulting in a notable decrease in
production cost and can even result in reduced scale up costs.
40
Productivity
20
Conventional
HPMCAS
High Productivity
HPMCAS
0
8
10
12
14
16
18
20
Polymer Concentration (wt %)
Figure 11. Comparison of viscosity of conventional HPMCAS 912 with
AFFINISOL High Productivity HPMCAS 912.
While increasing the spray drying throughput, AFFINISOL™
High Productivity HPMCAS maintains the same performance as
conventional HPMCAS. In a spray drying nozzle demonstration,
Figure 12A, a federate comparison increasing the concentration
of AFFINISOL™ High Productivity HPMCAS by 1.7x compared to
conventional HPMCAS results in identical nozzle feed performance.
The glass transition temperature (Tg) of AFFINISOL™ High
Productivity HPMCAS shows a reduction when compared to the
Tg of conventional HPMCAS but is still sufficiently high to provide
excellent stability to spray dried dispersions (Figure 12B).
A.
60
B.
130
300
290
HP-HPMCAS
110
270
100
260
250
240
90
80
230
70
220
60
210
200
200
Conventional HPMCAS
120
Tg (°C)
Feedrate (mL/min)
280
Conventional HPMCAS
HP HPMCAS - 1.5.1 wt%
300
400
Nozzle Pressure (PSIg)
500
600
50
0
20
40
60
80
Relative Humidity (%)
Figure 12. A. Spray drier nozzle comparison of conventional HPMCAS 912 at 9 wt % in acetone and AFFINISOL™ High Productivity HPMCAS 912 at 15.1 wt % in acetone.
A 1.7x increase in concentration results identical nozzle performance. B. A comparison of the Tg of conventional HPMCAS 912 with AFFINISOL™ High Productivity
HPMCAS 912.
9
Dow Pharma & Food Solutions
Spray dried dispersions formed with AFFINISOL™ High Productivity HPMCAS have similar solubility enhancement performance
to conventional HPMCAS. This is demonstrated by comparing the dissolution profiles of 25 wt % itraconazole amorphous solid
dispersions formed with conventional HPMCAS and AFFINISOL™ High Productivity HPMCAS (Figure 13A). The curves overlay
giving equivalent solubility enhancement and performance. Similar tests were also performed with phenytoin and ketoconazole.
The relative dissolution performance for each drug was identical for dispersions of conventional HPMCAS and AFFINISOL™ High
Productivity HPMCAS (Figure 13B).
A.
B.
1,000
Relative Dissolution Performance
Conventional HPMCAS
800
Concentration (μg/mL)
Conventional HPMCAS
HP-HPMCAS
HP-HPMCAS
600
400
200
0
0
60
120
180
240
300
360
Time (min)
Phenytoin
Itraconazole
Ketoconazole
Figure 13. A. Comparison of the dissolution profiles of 25 wt % itraconazole spray dried dispersions with conventional HPMCAS and AFFINISOL™ High Productivity HPMCAS
demonstrating identical behavior. B. Relative performance of dissolution comparing spray dried dispersions of phenytoin, itraconazole and ketoconazole with both conventional HPMCAS
and AFFINISOL™ High Productivity HPMCAS.
Incompatibilities
Packing and Shipping
AFFINISOL™ HPMCAS is incompatible with strong acids,
bases and strong oxidizing agents.
AFFINISOL™ HPMCAS is moisture sensitive and is produced
and packaged with a moisture content that meets the product
specification. The material is sold packaged in 25 kg high
density polyethylene (HDPE) drum with gasket sealed lid. As
a further barrier to moisture, the drum is double lined with
HDPE bags. The AFFINISOL™ HPMCAS grade and lot number
appears on the label.
Stability and Storage
AFFINISOL™ HPMCAS should be stored in a sealed container
that prevents moisture from entering the packaging to
prevent hydrolyzing the polymer. The container should be
kept away from heat, sparks and flames. Good housekeeping
should be practiced and all dust should be controlled as
AFFINISOL™ HPMCAS can generate hazardous dust causing
potential explosions.
Exposure Controls
Consult the MSDS for AFFINISOL™ HPMCAS for proper personal
protection equipment. Read and understand the MSDS
information prior to use.
10
Toxicology
No adverse effects were observed in several toxicological
studies performed with HPMCAS in animals. Studies
have included chronic, reproductive and developmental
investigations with doses up to 2500 mg/kg of body weight.
[5-10] In addition, the current Inactive Ingredient Database limit
for HPMCAS as an oral dosage form is 560 mg per day.
AFFINISOL™
References
1. Curatolo, W., J. Nightingale, and S. Herbig, Utility of Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS) for Initiation and Maintenance of Drug Supersaturation in the GI Milieu. Pharmaceutical Research, 2009. 26(6): p. 1419-1431.
2. Friesen, D.T., et al., Hydroxypropyl Methylcellulose Acetate Succinate-Based Spray-Dried Dispersions: An Overview.
Molecular Pharmaceutics, 2008. 5(6): p. 1003-1019.
3. Dahan, A., et al., The Twofold Advantage of the Amorphous Form as an Oral Drug Delivery Practice for Lipophilic
Compounds: Increased Apparent Solubility and Drug Flux Through the Intestinal Membrane. The AAPS Journal, 2013. 15(2):
p. 347-353.
4. Porter III, W.W., et al. Effect of Acetate and Succinate Substitution Levels On Spray Dried Dispersions of Hypromellose
Acetate Succinate – A Quality by Design Approach. in 2012 AIChE Annual Meeting. 2012. Pittsburgh, PA USA.
5. Hoshi, N., et al., EFFECTS ON OFFSPRING INDUCED BY ORAL ADMINISTRATION OF HYDROXYPROPYLMETHYLCELLULOSE
ACETATE SUCCINATE TO THE FEMALE RATS IN PERI-AND POST-NATAL PERIODS. The Journal of Toxicological Sciences, 1985.
10(SupplementII): p. 235-255.
6. Hoshi, N., et al., TERATOLOGICAL STUDY OF HYDROXYPROPYLMETHYLCELLULOSE ACETATE SUCCINATE IN RABBITS. The
Journal of Toxicological Sciences, 1985. 10(SupplementII): p. 227-234.
7. Hoshi, N., et al., TERATOLOGICAL STUDIES OF HYDROXYPROPYLMETHYLCELLULOSE ACETATE SUCCINATE IN RATS. The
Journal of Toxicological Sciences, 1985. 10(SupplementII): p. 203-226.
8. Hoshi, N., et al., STUDIES OF HYDROXYPROPYLMETHYLCELLULOSE ACETATE SUCCINATE ON FERTILITY IN RATS. The
Journal of Toxicological Sciences, 1985. 10(SupplementII): p. 187-201.
9. Hoshi, N., et al., GENERAL PHARMACOLOGICAL STUDIES OF HYDROXYPROPYLMETHYLCELLULOSE ACETATE SUCCINATE
IN EXPERIMENTAL ANIMALS. The Journal of Toxicological Sciences, 1985. 10(SupplementII): p. 129-146.
10. Hoshi, N., et al., TOXICOLOGICAL STUDIES OF HYDROXYPROPYLMETHYLCELLULOSE ACETATE SUCCINATE : ACUTE
TOXICITY IN RATS AND RABBITS, AND SUBCHRONIC AND CHRONIC TOXICITIES IN RATS. The Journal of Toxicological
Sciences, 1985. 10(SupplementII): p. 147-185.
11
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