Indo Amorphous

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when the drug is dissolved at a molecular level,

that is, when the drug forms one phase system

with polymer. In order to qualify as solid solution,

the drug/polymer system should satisfy the

following criteria:

(a) The mixtures of drug and polymer shouldshow single glass transition temperature.

(b) The drug should be present in amorphous

form.12,13

The improvement in bioavailability with solid

solution is primarily improvement in the dissolu-

tion rates and solubility due to the presence of

high-energy amorphous form.14 Comparing crys-

talline and amorphous solids, the three-dimen-

sional long range order that normally exists in a

crystalline material does not exist in the amor-

phous state. In other words, the amorphous solidshave macroscopic properties of a solid with the

microscopic structure of a liquid. By the virtue of

high internal energy, the amorphous solids

possess enhanced thermodynamic properties,

molecular motions, and chemical reactivity as

compared to crystalline solids.14

Since molecules in the amorphous state are

thermodynamically metastable as compared to

crystalline state, the potential for crystallization

during processing and storage is always present.

Hancock et al. have published extensive informa-

tion regarding the factors affecting stabilization of

amorphous state.1416 The critical factors affect-

ing stability of amorphous state are the Tg,hygroscopicity, purity and storage conditions.

The presence of moisture can show plasticization

effect and lower the Tg, which can increase theprobability of conversion of amorphous state to

crystalline state. The Tg of the drug can beincreased by adding polymers with high Tgvalues.In drug/polymer system, the stability of the

amorphous form primarily depends on criteria

such as drug and polymer interaction, viscosity of

polymer, and glass transition temperature of the

mixture.1719 The literature has shown thathigher glass transition temperature and higher

viscosity of polymers usually show superior

stability for the amorphous drug.14,15 The specific

interactions between drug and polymer are

important considerations for stabilization of the

amorphous formulation. Therefore the evaluation

and selection of polymer is a key factor in

developing solid solution.

For this study the hot-melt extrusion technology

was utilized to prepare solid solution of the poorly

water-soluble model drug. This technology employs

application of high shear and high temperature to

formulate solid solutions. This technology has

many advantages over traditional processing

techniques such as spray drying or coevaporation

which involves organic solvents. Some of the

important advantages are solvent free continuousprocess and relatively smooth scale-up.

The primary objective of this study was to

obtain stable solid solution of poorly water soluble

and low Tg model drug with water insoluble/ionicpolymer and water soluble/non ionic polymers.

The secondary objective was to evaluate perfor-

mance attributes of solid solutions as a function of

polymer-type and concentrations.

INM was selected as the poorly water-soluble

model drug and Eudragit EPO (EPO), polyvinyl-

pyrrlidonevinyl acetate (PVPVA), and polyvi-

nylpyrrolidone K30 (PVPK30) were selected ashydrophilic polymers.

MATERIALS AND METHODS

Materials

INM was purchased from Ria International LLC.

(Whippany, NJ). EPO was purchased from Rohm

America (Degussa Corporation, Parsippany, NJ).

PVPVA (Plasdone S630) was supplied by ISP

Corporation (Wayne, NJ) and PVP K30 was

purchased from BASF Corporation (FlorhamPark, NJ). All other chemicals used were of

analytical grade. The physicochemical proper-

ties of the drug and polymers used in the study are

tabulated in Table 1.

Methods

Preparation of Physical Mixtures

The drug and polymers were passed through a 60-

mesh screen and mixed thoroughly in a mortar

with pestle. These mixtures were further mixed inturbula mixer for additional 20 min. The different

ratios of drug to polymer prepared for the study

were: 30:70, 50:50, and 70:30.

Preparation of Melt Extrudates

Hot-melt extrusion was performed in Micro-18

twin screw corotating extruder (American Leis-

tritz Extruder Corporation, Somerville, NJ). The

extrusion barrel was divided in eight temperature

zones. The extrusion temperatures varied for

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 6, JUNE 2008

STABILIZATION OF LOW GLASS TRANSITION TEMPERATURE INDOMETHACIN FORMULATIONS 2287


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various polymers although they were kept above

Tgof the polymers. The extrusion screw speed waskept at 5560 rpm and K-Tron-automated gravi-

metric feeder was used to feed the material in melt

extruder at 56 g/min. The process parameters

such as motor load and melt pressures were

recorded for each formulation (Tab. 2). INM was

extruded with various polymers such as EPO,

PVPVA, and PVPK30 as binary mixtures at drug

to polymer ratios of 70:30, 50:50, and 30:70.

Milling of Hot-Melt Extrudates

The resultant extrudates were cooled on air

conveyor belt and milled using FitzMill1 Commi-

nutor (South Plainfield, NJ). The milling process

consisted of two passes, first pass with a sieve # 2

(sieve size 0.065 inch, coarse milling) and second

pass with a sieve # 1 (sieve size 0.033 inch, fine

milling).

Thermal Analysis

Thermal analysis was carried out using a SII 5200

DSC (TA Instruments, Newcastle, DE), equipped

with a liquid nitrogen-cooling accessory. Samples

(510 mg) were prepared in sealed pans. The

samples were scanned at a heating rate of 108C/

min. The data were treated mathematically using

the DSC 5200 Disk Station Analysis program.

Powder X-Ray Diffraction (PXRD)

The various samples were analyzed by PXRD

(Scintag Inc., Cupertino, CA) using Cu Karadiation to determine the crystalline or amor-

phous state of the drug in the melt extrudate. The

PXRD patterns were collected in the angular

range of 1< 2u< 408 in step scan mode (step width

0.028, scan rate 1 deg/min).

FT-IR Spectroscopy

These studies were helpful in elucidating the

interaction between the drug and polymers. IR

absorbance spectra were obtained using Perkin

Elmer, Spectrum GX series spectrometer

equipped with DTGS detector. The test solid

(0.81%) was mixed with KBr and analyzed using

the diffuse reflectance method. Fifty scans were

collected for each sample at a resolution of 4 cm1

over wave number region 4000400 cm1.

Solubility Studies

The solubility of the various melt extrudates were

performed in simulated gastric fluid (SGF) at

pH 1.5 (SGF) and simulated intestinal fluid at

pH 6.8 (SIF). An excess amount of formulation

was mixed with 20 mL of dissolution medium and

was shaken at ambient conditions in a mechanical

Table 1. PhysicoChemical Properties of the Drug and Polymers

PhysicoChemical Properties INM Eudragit EPO PVPVA PVPK30

Aqueous solubility Poorly soluble ($0.004 mg/mL) Soluble at pH


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shaker. The solubility of drug was measured after

24 and 72 h. The UV spectroscopy was used to

determine the solubility of the drug in dissolution

medium at 316 nm.

Dissolution StudiesIntrinsic dissolution or constant surface area

dissolution was studied using a Woods apparatus.

About 100 mg of the powder was compressed in

Woods apparatus die ($diameter 0.8 cm) using a

Carver Press at 4000 psi pressure and a dwell time

of 10 s. Dissolution was performed using a USP

Dissolution Apparatus II (Distek Inc., North

Brunswick, NJ) connected to HP UVVis spectro-

photometer Model 8452 (Hewlett-Packard Co.,

Palo Alto, CA) with a 900 mL of SGF with pH 1.5

and simulated intestine fluid (SIF) with pH 6.8 as

dissolution mediums at 378

C and a paddle speed of50 rpm.

Stability Studies

The accelerated stability studies were conducted

to determine the effect of high temperature and

humidity on the physical stability of the drug in

various formulations. The hot-melt extrudates

with various polymers and the drug as is were

stored at 408C/75% RH for 3 months in open glass

vials. For comparison purpose these formulations

were stored at controlled room temperature in

closed vials. Various analytical methods such asDSC, PXRD, and intrinsic dissolution studies

were used to access the stability of the formula-

tion.

RESULTS AND DISCUSSION

Evaluation of HME Process

The critical process parameters for various for-

mulations are listed in Table 2. The extrusion

temperature gradient, feed rate, and screw speed

were input parameters and motor load and meltpressures were output parameters. The extrusion

temperatures were dependent on glass transition

temperatures (Tg) of the polymers and thetemperature gradient across the barrel were kept

constant for each drug/polymer systems. The

extrusion temperatures were below the melting

point of INM. Feed rate and screw speed were kept

constant at 56 g/min and 5560 rpm, respec-

tively, for all formulations to ensure a constant fill

and shear in the extruder.20 Thus, motor load and

melt pressure were dependent on molecular mass

and viscosity of polymer and drug polymer

interactions.

The binary mixture with drug and polymer ratio

30:70 showed higher motor load and melt pressure

as compared to 50:50 and 70:30. Increasing the

concentration of drug decreased the motor loadand melt pressure, indicating a reduction in

viscosity of the polymer due to solubilization of

the drug. Since the molecular mass of EPO is

higher as compared to PVPVA and PVPK30

(Tab. 1), formulations with EPO showed higher

motor load.

Thermal Analysis

DSC was carried out to determine glass transition

temperature of the melt extrudates.

The crystalline INM showed an endotherm at

1658C and amorphous INM after heating and

quenching showed a glass transition temperature

(Tg) at 428C. EPO, PVPVA, and PVPK30 areamorphous in nature and showed Tg at 45, 109,and 1628C, respectively.

In case of melt extrudates with EPO, a single Tgwas observed suggesting the formation of solid

solution that is one phase system. However, the Tgof melt extrudate increased as a function of drug

concentration suggesting an antiplasticization

effect due to intermolecular interaction between

INM and EPO21 (Fig. 1). A similar effect was

observed with regards to the effect of temperatureon viscosity for INM and EPO system.22 Since

EPO is cationic and INM is a weak acid, a

potential for ionic interaction exists between

them23, however, no experimental evidence could

be obtained to confirm this hypothesis.

In case of melt extrudates with PVPVA and

PVP K30, a single Tg was observed indicatingformation of solid solution that is drug and

polymers were present in a one phase system.

INM acted as plasticizer for PVPVA and PVP

K30 and the Tgof melt extrudates were in between

the pure drug and pure polymers (Fig. 1).

Powder X-ray Diffraction Studies

Powder X-ray diffraction (PXRD) is an essential

technique in studying the crystalline or amor-

phous nature of the drug in solid solutions. The

PXRD for INM showed distinctive peaks at 10, 12,

13, 17, 19, 20, 21, 22, 23, 24, 27, and 29 degrees

indicating its crystalline nature as shown in

Figure 2. This figure also compares the corre-




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sponding PXRD of the INM, physical mixture, and

melt extrudate with EPO. The presence of drug

peaks in PXRD of physical mixture indicated

crystalline nature of the drug while absence of

peaks in melt extrudate suggested amorphous

nature of the drug in the melt extrudate.

Melt extrudates with various ratios of drug/

EPO, drug/PVPVA, and drug/PVPK30 showed

the absence of drug peaks, which indicated that

INM was present in an amorphous form (Fig. 3).

This observation further supported thermal ana-

lysis in confirming the formation of solid solution

of the drug with these polymers.

Based on thermal analysis and PXRD, it was

confirmed that INM formed one phase system

with these polymers and drug was present in

high-energy amorphous form.

FT-IR Studies

FT-IR studies were performed on various melt

extrudates to elucidate interactions between INM

and polymer and to confirm the crystalline or

amorphous nature of drug in the melt extrudate.

The crystalline INM showed strong CO bond

stretch at 1718 and 1692 cm1.When the INM was

converted to the amorphous form the C O bond

stretch shifted to 1709 and 1683 cm1.

The FT-IR studies of melt extrudates with EPO,

PVPVA, and PVPK30 showed the presence of

amorphous INM; however, there was no evidence

of interaction between drug and polymers.

Solubility Studies

INM is a weak acid (pKa 4.5) and shows pH-

dependent solubility. The INM solubility

increases with the increase in pH.22 The EPO is

cationic polymer and is soluble at pH less than 4

but permeable at higher pH. The PVPVA and

PVPK30 are nonionic polymers and has pH-

independent solubility. Therefore the solubility

studies were performed in two different pH

conditions: SGF pH 1.5 and phosphate buffer

SIF pH 6.2. The drug solubility from the various

formulations in SGF and SIF are shown in

Table 3.

The pure drug has negligible solubility in SGF,

however, shows a solubility of 1.06 mg/mL in SIF.

The melt extrudates with EPO showed

increased solubility in SGF. The increase in

solubility was dependent on EPO concentration.

The higher amount of EPO in the melt extrudate

increased the drug solubility in SGF. The melt

extrudate with drug to EPO ratio of 30:70 showed

significant increase in solubility compared to puredrug and 320-fold increase in solubility compared

to corresponding physical mixture after 72 h

(Tab. 3). The melt extrudates with drug to EPO

ratio of 70:30 and 50:50 showed lower solubility at

72h ascompared to 24h. Asshown in Figure 4 the

decrease in solubility may be attributed to the

partial conversion of amorphous drug to crystal-

line form in SGF at 72 h. However, there was no

change in solubility for 30:70 formulation even

after 72 hours suggested that amorphous drug

Figure 1. Phase diagram of melt extrudates with

EPO, PVPVA, and PVPK30. [Color figure can be seen

in the online version of this article, available on the

website, www.interscience.wiley.com.]

Figure 2. PXRD comparing INM, physical mixture,

and melt extrudate with EPO (drug:polymer 50:50).

[Color figure can be seen in the online version of this

article, available on the website, www.interscience.

wiley.com.]

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 97, NO. 6, JUNE 2008 DOI 10.1002/jps

2290 CHOKSHI ET AL.


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showed superior stability at high polymer con-

centration.

As shown in Table 3, the improvement of the

drug solubility in melt extrudate with INM/EPO

in SIF was significantly lower as compared to

SGF. In addition, the increase in solubility was

inversely related to polymer concentration. This

can be attributed to the poor solubility of EPO and

good solubility of the drug in SIF rather than the

instability of the amorphous form. This was

further confirmed by PXRD.The melt extrudates with PVPVA and PVPK30

did not show any significant improvement in

solubility in SGF indicating the instability of

amorphous form. The conversion of amorphous

form to crystalline form was confirmed by PXRD of

excess solids after 24 and 72 h (Fig. 5).

The melt extrudates with PVPVA and PVPK30

showed significant increase in solubility in SIF at

24 h (from 20-folds to 30-folds). However, the

solubility decreased at 72 h suggesting conversion

of the amorphous form to crystalline form. The

observed increase in solubility was inversely

related to polymer concentration at 24 h, which

was attributed to the high viscosity at high

Figure 3. PXRD of various melt extrudates with (a)

EPO (b) PVPVA (c) PVPK30. [Color figure can be seen

in the online version of this article, available on thewebsite, www.interscience.wiley.com.]

Table 3. Solubility of Various Formulations in SGF

and SIF after 24 and 72 h

Formulation

Solubility in

SGF in mg/mL

Solubility in

SIF in mg/mL

24 h 72 h 24 h 72 h

Indomethacin N/A N/A 1.06 1.0

Formulation with EPO, PM, and HME (drug:polymer)

PM 70:30 0.05 0.02 0.45 0.54

PM 50:50 0.07 0.04 0.36 0.47

PM 30:70 4.71 0.12 0.18 0.19

HME 70:30 0.21 0.15 2.74 2.68

HME 50:50 6.52 0.14 0.77 1.99

HME 30:70 41.72 38.31 0.26 0.22

Formulation with PVPVA, PM, and HME

(drug:polymer)

PM 70:30 0.00 0.00 1.77 1.53

PM 50:50 0.00 0.00 2.37 2.16

PM 30:70 0.01 0.00 2.51 2.70HME 70:30 0.00 0.03 14.27 3.91

HME 50:50 0.01 0.01 33.22 5.44

HME 30:70 0.01 0.02 8.87 6.37

Formulation with PVPK30, PM, and HME

(drug:polymer)

PM 70:30 0.00 0.00 1.35 1.25

PM 50:50 0.00 0.00 1.65 1.54

PM 30:70 0.01 0.00 1.55 1.61

HME 70:30 0.00 0.02 38.55 4.28

HME 50:50 0.04 0.05 34.31 4.00

HME 30:70 0.1 0.29 19.39 4.98

N/A, could not be detected; PM, physical mixture; HME,hot-melt extrudate.

Figure 4. PXRD of the various melt extrudate with

EPO in SGF after 72 h. [Color figure can be seen in the

online version of this article, available on the website,

www.interscience.wiley.com.]




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polymer concentration. Despite the conversion to

crystalline form, the equilibrium solubility from

melt extrudates was higher than the pure drug or

the corresponding physical mixtures. This may be

related to the stabilization of dissolved drug by the

polymer in the solution.

In summary, the melt extrudate with EPO

showed significant increase in solubility in SGF,

however, marginal increase was observed in SIF.

The high polymer concentration (EPO) helped in

stabilizing amorphous form of the drug even after

72 h during stability studies. On the contrary

PVPVA and PVPK30 did not show any signifi-

cant increase in solubility in SGF but these

formulations showed improved solubility in SIF.

However, the improved solubility could not bemaintained at 72 h.

Intrinsic Dissolution Studies

The intrinsic dissolution rates (IDR) of drug and

various formulations in SGF and SIF are sum-

marized in Table 4.

The IDR of the drug was 0.001 mg /cm2 min in

SGF, however, the dissolution rate increased by

40-folds in SIF.

The intrinsic dissolution profiles for melt

extrudate containing the drug and EPO are

shown in Figure 6. The thermal and PXRDanalysis of melt extrudate had shown that the

drug is present in amorphous form. Correspond-

ingly, the IDR of melt extrudates was found to be

significantly higher as compared to the pure drug

and the physical mixture in SGF. Furthermore,

the IDR were found to be dependent on polymer

concentration. The highest IDR was observed

with drug/EPO ratio of 50:50. The dissolution rate

increased by 2000-folds as compared to the pure

Figure 5. PXRD of the various melt extrudate with

PVPVA in SGF after 72 h. [Color figure can be seen in

the online version of this article, available on the web-

site, www.interscience.wiley.com.]

Table 4. Intrinsic Dissolution Rates for Various Formulations in SGF and SIF

Formulations IDR in mg/cm2 min in SGF IDR in mg/cm2 min in SIF

INM 0.0010.0005 0.040.01

Formulation with EPO, PM, and HME (drug:polymer)

PM 70:30 0.010.001 0.080.004

PM 50:50 0.060.01 0.050.002

PM 30:70 0.040.01 0.020.001

HME 70:30 1.470.04 0.010.002

HME 50:50 2.210.13 0.010.001

HME 30:70 1.790.21 0.010.002

Formulation with PVPVA, PM, and HME (drug:polymer)

PM 70:30 0.010.001 0.080.003

PM 50:50 0.010.001 0.170.01

PM 30:70 0.010.003 0.270.01

HME 70:30 0.010.001 0.940.16HME 50:50 0.010.002 1.130.19

HME 30:70 0.010.001 0.650.09

Formulation with PVPK30, PM, and HME (drug:polymer)

PM 70:30 0.0030.001 0.080.004

PM 50:50 0.010.003 0.140.01

PM 30:70 0.010.001 0.260.06

HME 70:30 0.010.002 1.040.05

HME 50:50 0.010.003 0.910.07

HME 30:70 0.010.003 0.300.01

PM, physical mixture; HME, hot-melt extrudate.


2292 CHOKSHI ET AL.


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drug and 35-folds as compared to the correspond-

ing physical mixture (Tab. 4). The increase in IDR

was directly related to the EPO concentration up

to 50:50. The IDR was slightly lowered at higher

polymer concentration (70%), which could be

attributed to high polymer viscosity and thus

lower drug diffusivity (Tab. 4 and Fig. 6).

The dissolution profiles of melt extrudates

showed tendency to revert back to crystalline

form in SGF. This finding is consistent withliterature data where metastable amorphous form

has been shown to crystallize out from super-

saturated solution. For the drug/EPO formula-

tions, the conversion to crystalline form were

directly related to the polymer concentration. The

time to reversion increased with increase in the

polymer concentration. In spite of the reversion,

the equilibrium solubility of the drug in dissolu-

tion medium was higher than the pure crystalline

form.

The IDR of drug/EPO melt extrudate in SIF were

lower than the pure drug, despite the higher drug

solubility of the drug in SIF (Tab. 4). A decrease in

IDR from melt extrudate indicates that the drug is

bound to polymer and the low dissolution rate is due

to the insolubility of the polymer in SIF and not the

physical instability of INM.


did not show significant improvement in IDR as

compared to the pure drug and the correspondingphysical mixture in SGF (Tab. 4). The low

dissolution rate was attributed to the conversion

of amorphous drug to stable crystalline form

during the dissolution.


showed an improved IDR as compared to pure drug

and corresponding physical mixtures in SIF. In the

case of PVPVA, the melt extrudate at the ratio of

50:50 showed 28-folds higher IDR as compared to

the pure drug and 7-folds higher as compared to

Figure 6. Dissolution profile comparing various compositions of melt extrudates with

EPO in SGF. [Color figure can be seen in the online version of this article, available on

the website, www.interscience.wiley.com.]




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the corresponding physical mixture (Tab. 4). In the

case of PVPK30, the melt extrudate at the ratio of

50:50 showed 23 fold higher IDR as compared to

the pure drug and 7 fold higher as compared to

corresponding physical mixture (Tab. 4). The

increasing polymer concentration showed decrease

in IDR (Figs. 7 and 8). Despite the similarity in

PVPK30 and PVPVA system, the different trends

were observed for IDR as a function of polymer

concentration. The PVPVA system showed an

increase in IDR up to 50% polymer concentration

followed by a decrease in IDR at 70% polymer


PVPVA in SIF. [Color figure can be seen in the online version of this article, available on



PVPK30 in SIF. [Color figure can be seen in the online version of this article, available on



2294 CHOKSHI ET AL.


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concentration. However, in the case of PVPK30,

IDR decreased as function of polymer concentra-

tion from 30% to 70 %. This can be attributed to

higher glass transition temperature and thus lower

drug mobility of the drug in PVPK30 system as

opposed to PVPVA system.

To confirm the physical stability of the INM

during dissolution, a small amount of surface

material was recovered and was analyzed by

PXRD. The melt extrudates with EPO at all ratios

showed the presence of amorphous drug in SGF

and SIF (Fig. 9). However, the drug in melt

extrudate with PVPVA and PVP K30 was

converted to crystalline form at the surface during

the dissolution studies (Fig. 10).

The solid solutions with EPO, PVPVA, and

PVPK30 showed improved dissolution rate due to

conversion to the high-energy amorphous form of

the drug. The amorphous INM in solid solutions

showed tendency to convert back to crystalline

form, which was dependent on dissolution media,

nature, and concentration of polymer.

Stability Studies

Stability studies were carried out to establish the

physical stability of the amorphous drug at the

accelerated conditions. All formulations were

stored at 408C and 75% relative humidity condi-

tions for 3 months in an open vial. Various

analytical techniques were used to monitor the

physical stability of the amorphous drug, such as

DSC, PXRD, and IDR studies.

After 3 months accelerated stability, the melt

extrudate of drug with EPO showed no depression

in glass transition temperature as compared to

the initial samples (Tab. 5). PXRD also confirmed

the amorphous nature of INM on stability. The

consistent solid-state properties after storage ataccelerated conditions suggest that amorphous

IND was stable in melt extrudate with EPO. This

was further confirmed by IDR studies showing

similar dissolution rates for initial and stability

samples (Tab. 6 and Fig. 11).

The melt extrudates with PVPK30 and PVPVA

stored at accelerated conditions displayed a

slightly lower glass transition temperature com-

pared to the initial samples (Tab. 5). That can be

attributed to the hygroscopic nature of the

Figure 9. PXRD of melt extrudates with EPO in SIF.

[Color figure can be seen in the online version of this

article, available on the website, www.interscience.

wiley.com.]

Figure 10. PXRD of melt extrudates with PVPK30 in

SGF. [Color figure can be seen in the online version of

this article, available on the website, www.interscience.

wiley.com.]

Table 5. Glass Transition Temperature Comparing

Initial and 3 Months 408C/75% RH Formulations

Formulations

Tg in 8C

Initial

Tg in 8C 3 Months

408C/75% RH

Formulation with EPO HME (drug:polymer)

HME 70:30 62.30.3 63.6 0.2HME 50:50 55.30.7 57.20.5

HME 30:70 45.90.5 47.80.6

Formulation with PVPVA HME (drug:polymer)

HME 70:30 59.40.7 58.80.4

HME 50:50 71.10.3 69.70.3

HME 30:70 80.80.9 76.50.6

Formulation with PVPK30 HME (drug:polymer)

HME 70:30 74.80.3 72.90.7

HME 50:50 92.90.6 90.20.9

HME 30:70 115.20.8 110.50.8

HME, hot-melt extrudate.




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polymer. However, PXRD confirmed the amor-

phous nature of the drug in stability samples. The

IDR after 3 months storage at accelerated

condition were similar to that of initial formula-

tions with lower concentration of polymer that is

drug to polymer ratio of 70:30 and 50:50 (Tab. 6).

However, the formulation with higher amount of

polymer (30:70) showed slight decrease in IDR in

SIF (Tab. 6, Figs. 12 and 13). The observed

decrease in IDR for 30:70 ratio was 1.6-fold and

15-folds for PVPVA and PVPK30 system, respec-

tively. This could be attributed to the hygroscopic

nature of the polymer. The higher concentration of

polymer will absorb more water and hence less

protection is provided to the amorphous drug.

To further evaluate this hypothesis, the moisture

content of stressed samples was determined by Karl

Fischer technique. As shown in Figure 14, the melt

extrudates with higher amount of polymer tend to

absorb more water, thus mediating the conversion

of amorphous drug to crystalline form.

Furthermore, PVPK30 system showed biphasic

dissolution profile. During the dissolution 1.8-fold

decrease in IDR (from 0 to 40 min and 4080 min)

was observed for both initial and stability sample

(Fig. 13). This observed decrease in dissolution

Table 6. IDR Comparing Initial and 3 Months 408C/75% RH Formulations in SGF

and SIF

Formulations IDR in mg/cm2 min Initial

IDR in mg/cm2 min

3 Months 408C/75% RH

Formulation with EPO HME in SGF drug:polymer

HME 70:30 1.470.04 1.520.12HME 50:50 2.210.13 2.130.21

HME 30:70 1.790.21 1.630.06

Formulation with PVPVA HME in SIF drug:polymer

HME 70:30 0.940.16 0.920.01

HME 50:50 1.130.19 1.090.16

HME 30:70 0.650.09 0.420.06

Formulation with PVPK30 HME in SIF (drug:polymer)

HME 70:30 1.040.05 1.100.11

HME 50:50 0.910.07 0.980.17

HME 30:70 0.300.01 0.020.01

HME, hot-melt extrudate.

Figure 11. The dissolution profile comparing initial

and 3 months 408C/75% RH melt extrudate with EPO in

SGF. [Color figure can be seen in the online version of

this article, available on the website, www.interscience.

wiley.com.]

Figure 12. The dissolution profile comparing initial

and 3 months 408C/75% RH melt extrudate with PVP

VA in SIF. [Color figure can be seen in the online version

of this article, available on the website, www.

interscience.wiley.com.]


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rates suggested that the rate-controlling mechan-

ism is consistent for both samples but different

from storage-mediated changes. This could be due

to differential dissolution rate of drug and

polymers resulting in drug-enriched surface layer

during dissolution.

SUMMARY AND CONCLUSION

The hot-melt extrusion was proven to be efficient

technology to formulate and stabilize the solid

solutions of low Tg model drug INM with theselected polymers such as EPO, PVPVA, and

PVPK30.

The drug formed one phase system that is solid

solution with EPO, PVPVA, and PVPK30 and

was found to be present in amorphous form at

various ratios.

The IDR and solubility were significantly

improved in case of solid solution that was

attributed to the high-energy amorphous form

of the drug. Although, melt extrudates with EPO

showed comparatively lower glass transition

temperature, these formulations showed superiorstability. Higher amounts of EPO in the formula-

tions facilitated stabilization of the amorphous

form of the drug. The melt extrudates with PVP

VA and PVPK30 showed higher glass transition

temperatures, however, these formulations were

more susceptible to conversion during dissolution

or storage stability.

In conclusion, the solid solutions improved the

solubility and IDR of the poorly water-soluble

model drug. The glass transition temperature was

Figure 13. The dissolution profile comparing initial and 3 months 408C/75% RH melt

extrudate with PVPK30 in SIF. [Color figure can be seen in the online version of this

article, available on the website, www.interscience.wiley.com.]

Figure 14. The moisture content of the melt extru-

dates comparing initial and stability samples. [Color

figure can be seen in the online version of this article,

available on the website, www.interscience.wiley.com.]




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not the only factor determining the stability of the

formulations but also nature and concentration of

polymer played a vital role in stabilizing the

amorphous nature of the drug.

Thus, the model drug with low Tg such as INM(428C) can be stabilized by the appropriate

selection of polymer and concentration.

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