AquaSolve as Handbook

8/10/2019 AquaSolve as Handbook

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AquaSolve andAquaSolve AS

hydroxypropylmethylcellulose acetate succinate

Physical and chemical properties

handbook

With good chemistry great things ha


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AquaSolve and AquaSolve AS Hydroxypropylmethylcellulose Acetate Succinate

I N T R O D U C T I O N . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

C H E M I S T RY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Origin6Manufacturing

Grades and Types

PHYSICOCHEMICAL PROPERTIES.. . . . . . . . . . . . . . . . . . . . . . . . . . .6

Product Specications

Morphology

Moisture Absorption

Thermal Properties

Glass Transition Temperature

Thermal Decomposition TemperatureMelt 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

Table of Contents


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4 AquaSolve and AquaSolve AS Hydroxypropylmethylcellulose Acetate Succinate

Introduction

AquaSolve (AquaSolve AS in the United Kingdom)hydroxypropylmethylcellulose acetate succinate (HPMCAS; knownas hypromellose acetate succinate in pharmaceutical applications)

is a mixture of acetic acid and monosuccinic acid esters ofhydroxypropylmethyl cellulose in the form of a white to off-whitepowder or granules. It has a faint acetic acid-like odor and a barelydetectable taste. AquaSolve HPMCAS is available in several gradesvarying in extent of substitution of acetyl and succinoyl groups andin particle size (ne or granular).

AquaSolve HPMCAS can be used as a solid-dispersion carrier forbioavailability enhancement of poorly soluble compounds. It isinsoluble in gastric uid, but will swell and dissolve rapidly in theupper small intestine. AquaSolve HPMCAS is commonly used asan enteric lm-coating agent for tablets, capsules and granules.

For aqueous lm-coating purposes, a dispersion of HPMCASne powder and plasticizer (such as triethyl citrate) in water iscommonly used. AquaSolve HPMCAS is also used in preparation ofsustained drug-release formulations. The release rate of the modeldrug from the matrix is pH dependent. Other formulation optionsinclude neutralized-solution/organic-solvent applications and dry-powder coating.

AquaSolve HPMCAS has the following functions and properties

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 bioavailabilityenhancement.

It is an enteric coating polymer.

These properties and functions make it suitable for use in manypharmaceutical applications. The polymer is available in threegrades: L, M and H, based on the content of acetyl and succinoylgroups (wt%) in the HPMCAS molecule. Each grade is availabletwo different particle sizes, F (ne) and G (granular).

This handbook describes basic chemical and physical properties AquaSolve HPMCAS. The range of types produced and the typicuses for this versatile cellulosic enteric polymer are also discussed


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Figure 1 shows the structure of the HPMCAS molecule; it isvisualized as a polymer chain composed of 2-hydroxypropoxygroups (-OCH2CH(CH3)OH), methoxy groups (-OCH3), acetyl groups

(-COCH3), and succinoyl groups (-COCH2CH2COOH).CASRN: 71138-97-1

CAS Name: Cellulose, 2-hydroxypropyl methyl ether, acetatehydrogen butanedioate

OriginAquaSolve HPMCAS is a synthetic polymer derived from cellulose,the most abundant polymer in nature. Highly puried cellulose pulpis reacted with methyl chloride and propylene oxide under alkalineconditions to produce hydroxypropylmethylcellulose (HPMC). TheHPMC is then used in a chemical sequence to produce AquaSolve

HPMCAS by reaction with acetic anhydride and succinic anhydride.

Chemistry

Figure 1 Structure of hydroxypropylmethylcellulose acetatesuccinate

ManufacturingAcetic anhydride and succinic anhydride are reacted withhydroxypropylmethylcellulose (HPMC) under specically controconditions to produce AquaSolve HPMCAS. The process beginswith cellulose, a polymer chain composed of repeating -1,4-anhydroglucose units. Each anhydroglucose unit contains threehydroxyl groups. The hydroxyl groups of HPMC used to makeHPMCAS are substituted with specic levels of methoxyl andhydroxypropoxy groups. The degree of substitution (DS) ofmethoxyl on HPMC ranges from 1.78 to 2.02 while the molarsubstitution of hydroxypropoxy is 0.23 to 0.41. The methoxyl DSinuences the amount of free hydroxyl groups available for furthesubstitution. Because the hydroxypropoxy group by denitioncontains a hydroxyl substitution, the level of hydroxypropoxysubstitution does not change the overall number of hydroxylgroups available for further substitution. When HPMC is reactedwith dened quantities and ratios of acetic anhydride and succinicanhydride, HPMCAS is produced, containing various levels of acand succinoyl esters.

Grades and TypesAquaSolve HPMCAS is produced in three substitution grades: L,and H. The three grades are insoluble in acidic aqueous solutionsAll three grades are soluble in dilute caustic solution, and to variodegrees in acetone and methanol. Each grade is available in ne (and granular (G) particle sizes. The range of grades is listed in Tab

1, according to the content of acetyl groups. The contents of theother major substituent groups are also listed in the table. Unlessotherwise noted, all percentages in this text are percentages byweight.

Table 1 AquaSolve HPMCAS grades

Grade AcetylContentSuccinoylContent

MethoxylContent

HydroxypropoxyContent

L 59% 1418% 2024% 59%

M 711 1014% 2125% 59%

H 1014% 48% 2226% 610%

OO

OO

n

RO

RORO

RO

OR

OR

R =H C(O)CH2CH2CO2H

CH3[CH2CH(CH3)O]mR

1C(O)CH3

R1=H C(O)CH3

CH3 C(O)CH2CH2CO2H


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Figure 2 shows the available grades of AquaSolve HPMCAS plottedby range of acetyl and succinoyl substitution levels.

Figure 2 Available grades of AquaSolve HPMCAS

Product SpecicationsDetailed product specications are listed in Table 2.

Table 2 Product specications

AquaSolve AS HPMCAS

LF and LG MF and MG HF and HG

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

Identication Conforms to U.S. National Formulary andJapanese Pharmacopoeia monographs

Viscosity1 2.43.6 mPas

Loss on Drying 5%

Residue on Ignition 0.20%

Heavy Metals < 10 ppm

Arsenic 2 ppm

Limit of Free Succinicand Acetic Acids 1.0%

Acetyl Content 59% 711% 1014%

Succinoyl Content 1418% 1014% 48%

Methoxyl Content 2024% 2125% 2226%

HydroxypropoxyContent 59% 59% 610%

Average Particle Size(Laser Diffraction) F

Types

10 microns

D90 (LaserDiffraction) F Types 20 microns

1 Measured for a 2% solution at 20C.

0

2

4

6

8

10

12

14

16

18

20

22

24

26

28

30

0 2 4 6 8 10 12 14 16 18 20

S u c c

i n o y l

C o n

t e n

t ( w t % )

Acetyl Content (wt%)

L Grade

M Grade

H Grade

Methoxyl range: 12-28%Hydroxypropoxy range: 4-28%

AquaSolve HPMCAS complies with National Formulary and Japanese PharmaceuticalExcipients specications (shaded box)

Ashland can tailor certain chemical and physical properties ofAquaSolve HPMCAS to meet users unique requirements. Usersare encouraged to discuss their needs with their Ashland technicalrepresentative, or to call the toll-free number shown on the backcover of this booklet for product information.

Physicochemical Properties


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Morphology The ne grind grades of AquaSolve HPMCAS are rounded toelongated particles ranging from approximately 0.50 to 1.50microns in diameter mixed with elongated to rounded fairly denseagglomerates ranging up to around 10.0 microns in diameter. Thecoarse grind grades of AquaSolve HPMCAS consist of large, fairlydense, rounded and slightly elongated agglomerates ranging upto approximately 1.60 mm in length. The ne elongated to roundparticles that form the agglomerates range up to around 30.0microns in length. Representative samples of AquaSolve MF andMG HPMCAS are shown in Figures 3 and 4.

Figure 3 SEM imagery for AquaSolve MF HPMCAS; for allF grades, D50 is near 5 m and D90 is near 10 m

Figure 4 SEM imagery for AquaSolve MG HPMCAS; for all Ggrades, particle size distribution is less than 1 mm

Moisture AbsorptionAquaSolve HPMCAS absorbs moisture from the air. The amountabsorbed and the rate of absorption depend on the initial moisturecontent and on the relative humidity and temperature of thesurrounding air. Figure 5 shows the effect of relative humidityon equilibrium moisture content of three grades of AquaSolveHPMCAS.

Figure 5 Effect of relative humidity on equilibrium moisturecontent of AquaSolve HPMCAS at 25C

10

)

8qua o v e

AquaSolve M HPMCAS n

t e n

t (

6 AquaSolve H HPMCAS

i s t u r e c

4

r i u m m

2 E q u

i l i

00 25 50 75 100

e a ve um y


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Thermal Properties

Glass Transition Temperature

Glass transition temperatures (Tg) of polymers were tested usingdifferential scanning calorimetry (DSC) under a nitrogen purgewith a TA Instruments DSC2000 calorimeter on 5 mg samples. Eachsample was heated at a rate of 20C/minute from 20C to 190Cand then cooled at the same rate back to 20C. After cooling,samples were held isothermal for 5 minutes and then heated againat the same rate to 195C. The glass transition temperature wasidentied as the half-height midpoint for the reheat data cycle. Allthree grades of HPMCAS have a Tg near 120C (Figure 6 and Table3). Glass transition temperature helps to guide the lower end of hot-melt extrusion processing temperature. Typically, hot-melt extrusionis processed about 2040C above Tg.

Figure 6 Glass transition temperatures for each grade of AquaSolve HPMCAS

Thermal Decomposition Temperature Thermal decomposition temperature (Td) was measured bythermogravimetric analysis (TGA). TGA was performed on 10 m

samples in a TA Instruments TGA Q5000IR* thermogravimetricanalyzer under N2 atmosphere. Nitrogen ow rate was 25 ml/minnormal air pressure with a heating rate of 10C/min. Samples werheated to above 800C until 5% weight loss, excluding moistureloss. All three grades of AquaSolve HPMCAS had decompositiontemperatures in the range of 258 to 276C (Figure 7 and Table 3). Thermal decomposition temperature denes the higher end of theextrusion temperature range.

Figure 7 Thermal decomposition temperatures for each grade o AquaSolve HPMCAS

119C

120C

122C

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

H e a

t F l o w

( W / g )

0

50

100

150

200

Temperature (C)

Exo Up

Universal V4.7A TA Instruments

AquaSolve L HPMCAS AquaSolve M HPMCAS AquaSolve H HPMCAS

Table 3 Glass transition and thermal decompositiontemperatures of AquaSolve HPMCAS

L Grade M Grade H Grade Tg 119 120 122

Td 258 267 276

258C

267C

276C

70

80

90

100

110

W e i g h

t ( % )

0

100

200

300

400

Temperature (C)

Universal V4.7A TA Instruments

AquaSolve L HPMCAS AquaSolve M HPMCAS AquaSolve H HPMCAS

Melt ViscosityMelt viscosity information can help to identify the hot-meltextrusion processing temperature window. The inuence of shearfrequency (shear rate; see Figure 8) and temperature (see Figure9) on melt viscosity were studied with a TA Instruments AR G2stress-controlled rotational rheometer, with a 25 mm parallel-plategeometry. The isothermal frequency sweep test was conductedat 170C with a frequency range from 0.1 rad/s to 600 rad/s and astrain in the linear viscoelastic region of the sample. All three graof AquaSolve HPMCAS show shear thinning behavior at 170C.


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Figure 8 Inuence of shear frequency on melt viscosity of AquaSolve HPMCAS at 170C

The temperature-sweep test was performed from 150C to 200Cwith a heating rate of 2C/min. The measurement frequency wasset at 6.28 rad/s and the strain was within the linear viscoelasticregion of each sample. All grades of AquaSolve HPMCAS hadmelt viscosities below 100,000 Pas at these temperatures,which is the generally accepted upper viscosity limit for hot-meltextrusion. Viscosities of all three grades decreased with increasintemperature from 150C to 200C. The melt viscosity of the H gris signicantly lower compared with the M and L grades, especiaat high temperatures.

Melt Viscosity with Various PlasticizersPolymer 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 gradof AquaSolve HPMCAS. All plasticizers effectively reduced the viscosity to below 100,000 Pas, making extrusion possible at lowtemperatures (around 120C) to improve processability.

Figure 10 Melt viscosity of AquaSolve L HPMCAS with variou plasticizers at 10%

1,000,000

100,000

i t y

( P a

s )

,

V i s c o

1,000 AquaSolve L HPMCASAquaSolve M HPMCAS

AquaSolve H HPMCAS

100.

Frequency (rad/s)

Figure 9 Melt viscosity of AquaSolve HPMCAS as a function oftemperature (measured at frequency of 6.28 rad/s)

100,000

i t y

( P a

s )

,

AquaSolve L HPMCAS V i s c o s

qua o v e

AquaSolve H HPMCAS

1,000150 160 170 180 190 200

Temperature (C)

100,000

1,000,000

10,000,000

AquaSolve L HPMCAS

With dibutyl sebacate

With diethyl phthalate

With triethyl citrate

With polysorbate 80

With Vitamin E TPGS

With distilled acetylatedmonoglycerides

i s c o s

i t y

( P a s

)

1,000

10,000

120 130 140 150 160 170 180 190 200

V

Temperature (C)


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Figure 11 Melt viscosity of AquaSolve M HPMCAS with various plasticizers at 10%

10,000,000 AquaSolve M HPMCAS

1,000,000



With trieth l citrate

With polysorbate 80

With Vitamin E TPGS y

( P a s

)

100,000 With distilled acetylatedmonoglycerides

V i s c o s

i t

10,000

,120 130 140 150 160 170 180 190 200

Temperature (C)

Figure 12 Melt viscosity of AquaSolve H HPMCAS with various plasticizers at 10%

10,000,000

AquaSolve H HPMCAS

1,000,000



With triethyl citrate

With polysorbate 80

With Vitamin E TPGS ( P a s

)

, With distilled acetylatedmonoglycerides

i s c o s

i t y

10,000

1 000120 130 140 150 160 170 180 190 200

Temperature (C)

Viscosity in Various SolventsA lower solution viscosity is advantageous for spray drying andcoating. The typical concentration of total solids for spray dryingis less than 10%, and concentrations of 3% to 5% are common.For lm coating, polymer concentration is generally less than 10%in solution. The viscosity of solutions of each grade of AquaSolvHPMCAS in various solvents was measured using a Brookeldviscometer. Results are shown in Figures 13 through 15. At 10%solids content, a viscosity less than 300 mPas indicates goodprocessability.

Figure 13 Viscosity of AquaSolve L HPMCAS at 20C in variosolvents

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

100

1000

10000

o s

i t y

( m P a s

)

Acetone

2:1 Ethanol:Acetone

8:2 Ethanol:Water

Methanol

2:1 Methylene chloride: Methanol

1

10

0 5 10 15 20

V i s c

HPMCAS concentration (%)

100

1000

o s

i t y ( m

P a s

)

Acetone

2:1 Ethanol:Acetone

8:2 Ethanol:Water

Methanol

2:1 Methylene chloride:Methanol

1

10

0 5 10 15 20

V i s c



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

100

1000

c o s

i t y

( m P a s

)

Acetone

2:1 Ethanol:Acetone

8:2 Ethanol:Water

Methanol

2:1 Methylene chloride:Methanol

1

10

0 5 10 15 20

V i


Solubility at Various pHPolymer solubility at various pH was evaluated by disintegration oflms in phosphate buffer solutions. Films were cast with acetoneas the solvent to a thickness of 90 m and cut into squares of 1.3cm. Disintegration time was measured using a USP disintegrationapparatus at 37C following general USP disintegration guidelines.Results varied by grade and pH, as shown in Figure 16.

40

60

80

100

120

AquaSolve LHPMCAS

AquaSolve MHPMCAS

AquaSolve HHPMCAS

n t e g r a

t i o n

t i m e

( m i n )

0

20

5 5.5 6 6.5 7 7.5 8

D i s i

pH of USP phosphate buffer

Film Strength The lms prepared for the dissolution testing were also used forlm tensile strength evaluations. Films were cast to a thickness of90 m. An Instron Universal Tensile tester was used to perform thevaluations. Results are described in Table 4. Aquasolve L, M, angrades of HPMCAS have similar lm characteristics.

Table 4 Film strength results

Grade of AquaSolveand AquaSolve ASHPMCAS

Elongation(%)

Modulus(MPa)

Yield Stress(MPa)

L 11 1574 35

M 19 1523 37

H 16 1494 40

Figure 16 Disintegration time of lms made from various gradeof AquaSolve HPMCAS


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Dissolution experiments were performed using a Pion DISSProler* dissolution apparatus. Spray-dried samples were added t20 ml of fasted-state simulated intestinal uid (FaSSIF) maintaineat 37C under a constant stirring speed of 300 rpm. A 2.0 mg modrug equivalent of each spray-dried powder was added to each viand drug concentration was measured by insitu ber optic probesat various time points.

For the solid dispersions of all three model compounds, L gradesconsistently gave the fastest initial dissolution (Figures 17 through19). The ability of the polymer to maintain supersaturation washighly dependent on the interaction between model drug andpolymer.

Figures 17 through 19 show the relative performance of AquaSolvHPMCAS with different substitution levels on solubilizationenhancement of model drugs with varying solubility.

Figure 17 Kinetic solubility results for spray-dried dispersions produced with itraconazole (ITZ) and each grade of AquaSolveHPMCAS at 25% drug load

160

180

140 l )

100

120

i o n

( g

/

25% Itraconazole AquaSolve L HPMCAS

80

n c e n

t r a

t i

25% Itraconazole AquaSolve H HPMCAS

Itraconazole API

40

C o

20 Solubility ofitraconazole: < 1 mg/l

0 50 100 150 200Time (minutes)

HPMCAS has been used as an enteric lm-coating polymer fortablets and also for capsules. Its effectiveness as a solid-dispersioncarrier for bioavailability enhancement has attracted the most

attention in recent years. Numerous publications have indicatedthat HPMCAS is able to initiate and maintain supersaturation fordrugs with a wide variety of structures and physical properties, andthe efficacy advantage of HPMCAS is primarily due to the polymerssuperiority as a precipitation inhibitor via the formation of colloidalspecies in aqueous media.1,2

Solid Dispersion for Bioavailability EnhancementAcetyl and succinoyl substitution levels have a signicant impacton the performance of HPMCAS as an amorphous solid-dispersioncarrier. This effect is demonstrated in a case study in which thedissolution performance of solid dispersions prepared by spraydrying using AquaSolve HPMCAS L, M and H grades and thepoorly soluble compounds ezetimibe (EZE), itraconazole (ITZ) andfelodipine (FEL) was evaluated. The acetyl to succinoyl ratios of theAquaSolve L, M and H HPMCAS grades were 0.48, 0.87 and 1.8,respectively.

Spray-drying solutions were prepared by dissolving modelcompound and polymer into 2:1 (w/w) dichloromethane:methanolsolution at 5% solids. Spray drying was performed on a GEA SDMicro* Spray-Dryer. The feed material was atomized using a 0.5 mmtwo-uid Schlick nozzle targeting an inlet temperature of 85C, aprocess gas ow of 25 kg/hr, an atomizing gas pressure of 0.5 bar,and an atomizing-gas ow rate of 1.5 kg/hr. The liquid-feed ratewas adjusted to maintain an outlet gas temperature of 55C. Afterspray drying, the spray-dried dispersions were vacuum dried for 48hours at 40C under 25 in. Hg reduced pressure.

The spray-dried powders were evaluated for the amorphouscharacteristics of the samples and the dissolution performance. Allspray-dried solid dispersions were characterized as amorphous byX-ray powder diffraction (XRPD) performed on a Bruker D8 Focusdiffractometer, using a copper tube element and a PSD LynxEye*detector.

Applications


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Figure 18 Kinetic solubility results for spray-dried dispersions produced with ezetimibe (EZE) and each grade of AquaSolveHPMCAS at 50% drug load

120

50% Ezetimibe and AquaSolve L HPMCAS

100

l )

50% Ezetimibe and AquaSolve M HPMCAS

50% Ezetimibe and AquaSolve H HPMCAS

80

n ( g

/ m

60

c e n

t r a

t i

40 C o n

Solubility ofezetimibe: 8.46 mg/l

0 50 100 150 200Time (minutes)

Figure 19 Kinetic solubility results for spray-dried dispersions produced with felodipine (FEL) and each grade of AquaSolveHPMCAS at 40% drug load

600

500

l )40% Felodipine and AquaSolve L HPMCAS

400

n ( g

/ m l

40% Felodipine and AquaSolve H HPMCAS

Felodipine API

300

c e n

t r a

t i

200 C o n

100 Solubilityoffelodipine: 19.7 mg/l

0 50 100 150 200Time (minutes)

As indicated in Figure 17, the itraconazole solid dispersion had agreater area under the dissolution curve (AUC) when formulatedwith AquaSolve L and M grades of HPMCAS. Itraconazole is a

weakly basic compound that can form ionic interactions with thesuccinoyl groups of HPMCAS. The L and M grades have more reavailable succinoyl groups and rendered solid dispersions withbetter dissolution performance. Both ezetimibe (weak acid) andfelodipine (neutral) showed low AUCs with L grade solid dispersand higher AUC in M- and H-grade solid dispersions (Figures 18 19). For both compounds, M-grade solid dispersions performedsimilarly with H-grade solid dispersions. AquaSolve M and HHPMCAS are more hydrophobic than L grade, as indicated by thhigher acetyl to succinoyl ratios, and these two grades thereforehave stronger intermolecular interactions with hydrophobicezetimibe and felodipine and were able to maintain supersaturatiofor prolonged periods.It can be concluded from this case study that for basic compoundlike itraconazole, the L grade with more succinoyl groups canform ionic interactions and result in solid dispersions with betterdissolution performance. For hydrophobic compounds such asezetimibe and felodipine that are non-ionizable or acidic, the morhydrophobic H and M grades offer better performance due to thestrong interactions with the compounds. In addition, the dissolutiorate of the polymers has signicant impact on the dissolution rateof the solid dispersions.

Enteric Coating This case study was performed on tablets containing omeprazoleas the model drug. Omeprazole is a proton-pump inhibitor that isunstable in acidic conditions, making an enteric coating necessaryAn enteric coating dispersion formulation was prepared usinga neutralization method by adding basic agents. The coatingformulations are listed in Table 5 and were prepared as follows:triethyl citrate and sodium lauryl sulfate were added to water (atambient conditions) and stirred for 5 min. AquaSolve HPMCASand talc were added and stirred until uniformly distributed. Finallmonoethanolamine was added to the dispersion, pH was adjustedto pH 8 (target pH 79) with ammonium hydroxide and themixture was stirred for 3 h at ambient conditions until no HPMCAparticles were left. The nal step was ltration with a 20 mesh sieAlternatively, a 20 mesh screen can be placed at the end of the inltubing. The dispersion was gently stirred during the entire coatingprocess to prevent the precipitation of talc.


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Figure 20 Dissolution testing results for AquaSolve L HPMCAunder the U.S. Pharmacopoeia testing methods

100

80 ( % )

60 AquaSolve L HPMCAS r e l e a s e

d

40 p r a z o

l e

20

O m

0

pH 6.8

pH 1.2

0 30 60 90 120 150Time (min)

Figure 21 Dissolution testing results for AquaSolve M and HHPMCAS under the British Pharmacopoeia testing methods

100

80 % )

60 AquaSolve M HPMCAS

l e a s e

d (

40

AquaSolve H HPMCAS

r a z o

l e r e

20 O m e p

H 4.5

pH 6.8

00 15 30 45 60 75 90

Time (min)

Table 5 Omeprazole tablet coating formulations

Ingredient Percent by Weight

HPMCAS (L, M or H) 58.1Monoethanolamine 3.4

Triethyl citrate 14.8

Sodium lauryl sulfate 1.6

Talc 20.0

Ammonium hydroxide ~2.1

The formulations were coated on 300 mg tablets containing a 20mg dose of omeprazole, using the parameters listed in Table 6.

Table 6 Omeprazole tablet coating parameters

Parameter OHara LabCoat II

Pan size 15 inch

Gun Schlick 1.2 mm

Pan load (kg) 3

Pan speed (rpm) 14

Bed temperature (C) 4550

Spray rate (g/min) 20

Inlet temperature (C) 5560

Outlet temperature (C) 4345

Air volume (cfm) 175

Atomizing air pressure (psi) 30

Pattern air pressure (psi) 30

Final solution viscosity of the coating was 100 to 300 mPas with asolids content of 15%. Tablets were coated to a 20% weight gain.Omeprazole dissolution analysis with high-performance liquidchromatography (HPLC) was made to ensure compliance with theBritish and U.S. pharmacopoeia standards for drug release, detailedin Table 7. The L grade of AquaSolve HPMCAS was tested using theU.S. Pharmacopoeia (USP) method . The M and H grades weretested using the British Pharmacopoeia (BP) monograph for gastro-

resistant omeprazole tablets. Results of the dissolution testing areshown in Figures 20 and 21.

Table 7 Omeprazole tablet release criteria

BP Method 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%


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IncompatibilitiesAquaSolve HPMCAS is incompatible with strong acids or bases,oxidizing agents and sustained levels of elevated humidity.

Stability and Storage ConditionsAquaSolve HPMCAS should be stored in a well-closed container,in a cool, dry place. In such storage conditions, HPMCAS is a stablematerial. HPMCAS is hygroscopic and can hydrolyze to acetic acidand succinic acid over prolonged periods of time. Hydrolysis isthe main degradation pathway that is responsible for increasingamounts of free acids in storage, especially upon exposure tomoisture.

Packaging and Shipping The moisture content of AquaSolve HPMCAS does not exceed5% by weight when the products are packed. Because of varyingstorage and shipping conditions, there is a possibility of somemoisture pickup from the as-packed value. Although packaginghas been designed to reduce moisture pick up, product shouldbe stored under clean, dry conditions and used in rotation. The standard product packaging is 25 kg net weight sealedpolyethylene bags, shipped in drums. The type, lot number anddrum number are stenciled on the outside of each drum. Read andunderstand the Safety Data Sheet (SDS) before using this product.

Regulatory StatusAll AquaSolve HPMCAS grades conform to the monographrequirements of the current editions of the National Formularyand Japanese Pharmacopoeia. Please contact your Ashlandrepresentative for access to the Excipient Information Package (EIP)for further details.

ToxicologyAquaSolve hypromellose acetate succinate (HPMCAS) is insolublein water and this, combined with a molecular weight rangebetween 10,000 and 500,000 daltons, indicates that it is not orallybioavailable. There were no adverse effects in several toxicologicalstudies, including chronic or reproductive and developmentalanimal studies.39 HPMCAS is an approved pharmaceutical excipientfor oral dosage forms. The present Inactive Ingredient Databaselimit for HPMCAS is 560 mg per day.

References1. Friesen, D. T., R. Shanker, M. Crew, D. T. Smithey, W. J. Curatolo, and J. A. S. Nigh

Hydroxypropyl Methylcellulose Acetate Succinate-based Spray-dried Dispersions:

Overview. Molecular Pharmaceutics. 5 (2008): 10031019.2. Curatolo, W., J. A. Nightingale and S. M. Herbig. Utility of Hydroxypropylmethyl

Acetate Succinate (HPMCAS) for Initiation and Maintenance of Drug Supersaturatiothe GI Milieu. Pharmaceutical Research. 26 (2009): 14191431.

3. Hoshi, N., K. Ueno, H. Yano, K. Hirashima & H. Kitagawa. General PharmacologiStudies of Hydroxypropylmethylcellulose Acetate Succinate in Experimental AnimaJournal of Toxicological Sciences. 10(Suppl 2). (1985): 129146.

4. Hoshi, N., H. Yano, K. Hirashima, H. Kitagawa & Y. Fukuda. Toxicological StudieHydroxypropylmethylcellulose Acetate SuccinateAcute Toxicity in Rats and Rabband 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 & MTeratological Studies of Hydroxypropylmethylcellulose Acetate Succinate in Rats.Journal of Toxicological Sciences. 10(Suppl 2). (1985): 203226.

6. Cappon, G. D., T. L. Fleeman, M. S. Rocca, J. C. Cook & M. E. Hurtt. Embryo/FeDevelopment Studies with Hydroxypropyl Methylcellulose Acetate Succinate (HPMin Rats and Rabbits. Birth Defects Research Part B: Developmental and Reproduct Technology. 68. (2003): 421427.

7. Hoshi, N., K. Ueno, T. Igarashi, H. Kitagawa, T. Fujita, N. Ichikawa, Y. Kondo & MTeratological Study of Hydroxypropylmethylcellulose Acetate Succinate in RabbitsJournal of Toxicological Sciences. 10(Suppl 2). (1985): 227234.

8. Hoshi, N., K. Ueno, T. Igarashi, H. Kitagawa, T. Fujita, N. Ichikawa, Y. Kondo & MStudies of Hydroxypropylmethylcellulose Acetate Succinate on Fertility in Rats. Jof Toxicological Sciences. 10(Suppl 2). (1985): 187201.

9. Hoshi, N., K. Ueno, T. Igarashi, H. Kitagawa, T. Fujita, N. Ichikawa, Y. Kondo & MEffects on Offspring Induced by Oral Administration of HydroxypropylmethylcellAcetate Succinate to the Female Rats in Peri- and Post-natal Periods. Journal of Toxicological Sciences. 10(Suppl 2). (1985): 235255.


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