Pharmaceutical Development and Technology, 2009; 14(5): 499–505

R E S E A R C H A R T I C L E

Influence of sodium dodecyl sulfate on swelling, erosion and release behavior of HPMC matrix tablets containing a poorly water-soluble drug

Aiguo Zeng, Bingxiang Yuan, Qiang Fu, Changhe Wang and Guilan Zhao

School of Medicine, Xi’an Jiaotong University, Xi’an 710061, P. R. China

Address for Correspondence: Aiguo Zeng, School of Medicine, Xi’an Jiaotong University, Xi’an 710061, P. R. China. Tel.: +86-029-82655139. E-mail: agzeng@mail.xjtu.edu.cn

(Received 28 June 2008; revised 21 October 2008; accepted 20 January 2009)

Introduction

Hydroxypropylmethylcellulose (HPMC), a hydrophilic cellulose ether derivative with unique physico-chem-ical properties, is a polymer widely used in swellable hydrophilic matrix tablets for controlled release of drugs. On exposure to water or biological fluid, HPMC tablet becomes hydrated and swells. A swollen matrix can be divided into four components: the dry glassy core, the swollen glassy layer, the gel layer, and the diffusion layer separating the matrix from the media.[1] In the water-rich diffusion layer, the polymer concentration is so low that chain entanglement becomes weak. At the gel layer-diffusion layer interface, the weak chain entanglement can no longer hold polymers together and thus, poly-mer erosion takes place at this interface. The influence of various factors on the swelling, erosion and release behavior of HPMC matrix tablets have been investigated.

These factors include polymer content,[2] viscosity of the polymer,[3,4] particle size of polymer,[5,6] presence of other polymers and excipients,[7] solubility of the drug,[8] surface area and shape of the matrix tablets,[9] manufac-turing process variables (method of incorporating raw materials, blending time, compression force, etc.),[10,11] and conditions for dissolution studies.[12]

SDS, as an anionic surfactant, is usually added into dissolution media to improve solubility of poorly water-soluble drugs. However, SDS may alter the swelling and erosion of HPMC matrix tablets. For example, increas-ing the concentrations of inorganic ions in a dissolu-tion medium was shown to decrease the erosion rate of HPMC matrix tablets due to the ‘salting out’ of the polymer by the inorganic ions.[12] However, little stud-ies reported in past how SDS in a dissolution medium would affect the swelling and erosion of HPMC matrix tablets. On the one hand, SDS is expected to improve

ISSN 1083-7450 print/ISSN 1097-9867 online © 2009 Informa UK LtdDOI: 10.1080/10837450902773592

AbstractThe effect of sodium dodecyl sulfate (SDS) on the swelling, erosion and release behavior of HPMC matrix tablets was examined. Swelling and erosion of HPMC matrix tablets were determined by measuring the wet and subsequent dry weights of matrices. The rate of uptake of the dissolution medium by the matrix was quantified using a square root relationship whilst the erosion of the polymer was described using the cube root law. The extent of swelling decreased with increasing SDS concentrations in the dissolution medium but the rate of erosion was found to follow a reverse trend. Such phenomena might have been caused by the attractive hydrophobic interaction between HPMC and SDS as demonstrated by the cloud points of the solutions containing both the surfactant and polymer. Release profiles of nimodipine from HPMC tablets in aqueous media containing different concentrations of SDS were finally studied. Increasing SDS concentrations in the medium was shown to accelerate the release of nimodipine from the tablets, possibly due to increasing nimodipine solubility and increasing rate of erosion by increasing SDS concen-trations in the dissolution medium.

Keywords: HPMC; swelling; erosion; release; SDS; nimodipine

http://www.informahealthcare.com/phd

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500 A. Zeng et al.

the solubilities of poorly water-soluble drugs, thereby increasing dissolution rates of these drugs from oral solid dosage forms. On the other hand, the SDS contained within HPMC matrix tablets has been reported to hinder the release of soluble drugs from HPMC matrices.[13,14] The water-soluble drug may form poorly water-soluble complexes through ionic interactions with sodium alkyl sulphate and consequently delay drug release from the HPMC matrix tables. However little has been done to evaluate the effects of SDS in dissolution media on the release profiles of poorly water-soluble drugs from HPMC matrix tablets. In the present study, swelling and erosion of HPMC tablets in dissolution media contain-ing SDS were examined by measuring the wet and sub-sequent dry weights of HPMC tablets. Finally the effect of SDS on the release profiles of a poorly water-soluble drug (nimodipine, NM) from HPMC matrix tablets was investigated in dissolution media containing different concentrations of SDS.

Materials and methods

Materials

HPMC (Methocel K100M CR Premium USP/EP) was a gift from Shanghai Colorcon Coating Technology Ltd. (Shanghai, China), Nimodipine (NM) was obtained from Tianjin Zhongyang Pharmaceutical Company (Tianjin, China), Lactose (Tablettose 80, Meggle, Germany) was a gift from Beijing Infoark Technology Development Co., Ltd. (Beijing, China), sodium dodecyl sulfate and mag-nesium stearate were both obtained from Anhui Shanhe Medicinal Accessory Material Co., Ltd (Anhui, China).

Formulation and tablet preparation

The tablets each comprising 150 mg HPMC, 30 mg NM, 119 mg lactose and 1 mg magnesium stearate were pre-pared by direct compression on a single punch tablet press fitted with a flat punch of 9 mm diameter (Beijing Gylongli Pharmaceutical Machinery Co., Ltd, Beijing, China). Tablets were pressed to have crushing strengths in the range of 5–6 kP.

Tablets swelling and erosion characteristics

The reported methods were employed to characterize the swelling and erosion of the tablets.[15] In experiment, USP 30 apparatus II (paddle) was employed with a slight modi-fication where a stainless steel container with two opposite meshes was placed immediately below the paddle in the dissolution vessel.[16] Tablet was placed in the compart-ment formed by the two mesh surfaces of the container. The stirring speed was set at 100 rpm. The dissolution media contained varying SDS concentrations and each

medium was kept at 37°C. A total of 900 mL of dissolution medium was measured into each of the six vessels of the bath and allowed to equilibrate before starting the experi-ment. The tablet prepared above was weighed to obtain the initial weight (W

i) prior to each experiment. Then,

the tablet was immersed into the dissolution medium for predetermined time periods before it was removed into a pre-weighed weighing boat. The excess dissolution medium on tablet was removed by draining the tablet and wiping its edge carefully with paper without touching the tablet. The tablet and boat were then weighed to estab-lish the wet weight of the tablet (W

w). The tablet was then

dried to a constant weight in an oven at 60°C and the dry weight of tablets (W

d) were recorded. Each determination

at each time point was performed in triplicate.Several parameters were calculated to represent

the extent of swelling and erosion. The relative swell-ing, the ratio of the wet weight to the initial weight was determined, which was employed to reflect the extent of matrix swelling.[17]

Relative swelling = W

WW

i (1)

The dissolution medium uptake by tablet was obtained by subtracting the dry weight of the tablet from its wet weight at each time point:[15]

Dissolution medium uptake = W WW d− (2)

The ratio of medium content to matrix remaining in the tablet (Q

w, %) was calculated using Equation 3,

Q =W -W

WWW d

d (3)

The values for Qw

were plotted against the square root of time for the initial points[12] as in Equation 4.

Q =k tW 11/2

(4)

where k1 is the rate constant for the penetration rate of

the medium into the matrix tablet.The values of the dry weight were fitted to the cube

root relationship with time as outlined by Tahara et al.[15] to determine the apparent polymer erosion rate con-stant k

2 (Equation 5).

W

W= -k td

i2

1/3

1

(5)

Solubility determination

The solubility of nimodipine was determined in SDS solutions at various concentrations using a standardized

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Influence of SDS on HPMC matrix tablets 501

shake flask method at 37°C. After shaking for 48 h, the supernatant was then filtered through a 0.22 m mil-lipore membrane filter and the filtrate was diluted in ethanol and NM concentration in the diluted solution was measured spectrophotometrically at 238 nm using an ultraviolet spectrophotometer (UV-2450, Shimadzu, Japan).

Dissolution tests

The dissolution tests of the tablets were performed using the apparatus previously described with the paddle stir-ring rate being set at 100 rpm and dissolution media with varying concentrations of SDS. All dissolution tests were conducted at the dissolution medium temperature of 37°C. Samples (5 mL) were taken at predetermined timepoints and each sample was immediately replaced by the same volume of fresh dissolution medium. The samples from dissolution tests were filtered, and the NM concentrations in the solution were measured spec-trophotometrically at 238 nm using an ultraviolet spec-trophotometer. All dissolution tests were performed in triplicate.

Kinetic analysis

In order to characterize the drug release mode from the matrices, the data were fitted to the power law equation as shown in Equation 6:[18]

M /M =kttn

∞ (6)

Here, Mt and M

∞ are the absolute cumulative amount of

drug released at time t and infinite time, respectively; k is a constant incorporating structural and geometric characteristics of the table, and n is the release expo-nent, indicative of the mechanism of drug release.

Cloud point

Cloud point is the temperature at which the light trans-mission of a gel is reduced by 50% of the initial value.[19] Cloud point measurements were performed on 1% (w/v) HPMC gels in different dissolution media. Quantities of gels (100 g) were prepared by dispersing the pre-weighted polymer into approximately 50 mL distilled water previously heated to 80°C, adding distilled water containing the required amount of dissolved surfactants and making up to weight with distilled water. When cool, the weights were checked and more cool distilled water added if necessary. The gels were stored for 48 h in a refrigerator to allow it to hydrate fully. The samples were placed in a water bath and temperature was grad-ually increased. At 5°C intervals (or 2°C intervals when approaching the cloud point), sample transmittance was

measured spectrophotometrically at 800 nm using an empty glass cuvette as a blank and a 0% HPMC medium as the control.[7]

Results and discussion

Effect on erosion of HPMC tablets

In order to examine the effects of SDS on the erosion of HPMC tablets, erosion studies were conducted using aqueous media containing different concentrations of SDS. The effects of SDS on the erosion of HPMC tablets were represented by the percentage remaining of tab-lets after erosion (the percentage remaining of tablets = W

d/W

i × 100%) and the erosion rate constant (k

2). The

percentage remaining results showed that the tablets under investigation started to erode immediately after being immersed in any of the aqueous media contain-ing different concentrations of SDS without any lag period prior to the onset of erosion. The higher the con-centration of SDS, the lower the percentage remaining value was (Figure 1). The erosion rate constant (k

2) of

tablets in aqueous media containing different concen-trations of SDS were determined by fitting the cube of W

d/ W

i versus time data according to Equation (5). As

is shown in Figure 2, the k2 values increased with the

concentration of SDS (Table 1), suggesting that increas-ing SDS concentrations increased the rate of erosion of the tablets.

Thus, the influence of SDS on the erosion of HPMC tablets differs from that of inorganic ions. Inorganic ions are known to inhibit the erosion of HPMC tablets due to the ‘salting out’ effect on the polymer. In contrast, SDS was shown to promote the erosion of HPMC tablets. Löfroth et al.[20] reported that there existed an attrac-tive hydrophobic interaction between HPMC and SDS. When presented in an aqueous solution, a lot of SDS molecules are expected to penetrate into the water-rich

0102030405060708090

100

0 2 4 6 8 10 12 14 16Time (hours)

Water0.3%SDS0.5%SDS0.8%SDS1.0%SDS

Wd/

Wi (

%)

Figure 1. The ratios of the dry weight (Wd) to the initial weight (W

i)

for HPMC tablets (n = 3) at different timepoints after dissolution in aqueous media containing different concentrations of SDS.

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502 A. Zeng et al.

diffusion layer through diffusion and an attractive hydro-phobic interaction with the polymer. Because the HPMC concentration in the diffusion layer is extremely low, the polymer saturation point (PSP) in the diffusion layer is low, and the SDS concentrations in the diffusion layer is higher than PSP thereby reducing the viscosity of the dif-fusion layer. The higher the SDS concentration, the lower the viscosity of the diffusion layer.[21] A Similar effect of SDS on ethyl(hydroxyethyl)cellulose was also reported in a previous study.[22] Polymer erosion takes place at the gel layer-diffusion layer interface. The matrix dissolution flux, J

p, through the diffusion layer can be described as

follows:

J =f <D > v Cp p p2/3 1/6

p.disWapp

1/2− −

where < Dp > is the average diffusion coefficient of the

polymer within the diffusion layer.[1] According to the Stokes-Einstein relationship,[23] D

p is inversely related

to solvent viscosity (s). Decreasing solvent viscosity

increases Dp. Thus, increasing SDS concentrations in the

medium decreases the viscosity of the diffusion layer, which subsequently increases the average diffusion coefficient, leading to the increase rate of erosion of the polymer.

Effect on swelling of HPMC tablets

In order to examine the effect of SDS on the swelling of HPMC tablets, swelling studies were conducted using aqueous media containing different concentrations of SDS. The effect of SDS on the swelling of HPMC tablets was represented by the relative swelling (Figure 3), a parameter measuring the extent of tablet swelling after absorbing water from the dissolution media. The pres-ence of SDS in the medium reduced the water uptake and swelling of the matrix tablet. The extent of swelling in SDS aqueous media decreased with an increase in SDS concentrations.

The rate of water uptake per unit weight of polymer follows a declining, non-linear relationship with time whilst the cumulative water uptake is proportional to the square root of time during the initial phase (Figure 4). Water uptake profiles were therefore fitted

Table 1. The erosion parameters for HPMC tablets measured in aqueous media containing different concentrations of SDS stirred at 100 rpm.

SDS k2 (h−1) r2

0% 0.0236 0.9930

0.3% 0.0278 0.9974

0.5% 0.0297 0.9973

0.8% 0.0350 0.9953

1.0% 0.0394 0.9901

0

0.5

1

1.5

2

2.5

3

3.5

4

0 2 4 6 8 10 12 14 16

Time (hours)

Water

0.3% SDS

0.5% SDS

0.8% SDS

1.0% SDS

Ww/W

i

Figure 3. The ratios of the wet weight (Ww

) to the initial weight (Wi)

of HPMC tablets (n = 3) in aqueous media containing different con-centrations of SDS.

0

2

4

6

8

10

12

0 1 2 3 4

water0.3%SDS0.5%SDS0.8%SDS1.0SDS%

Time (hours0.5)

(Ww-W

d)W

d

Figure 4. The uptake of the dissolution medium by each unit of the polymer remaining in HPMC tablets, plotted versus t0.5 in aqueous media containing different concentrations of SDS stirred at 100 rpm.

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16Time (hours)

(Wd/

Wi)

^ (1

/3)

Water

0.3%SDS

0.5%SDS

0.8%SDS

1.0%SDS

Figure 2. The cube of the ratios of the dry weight (Wd) to the initial

weight (Wi) of HPMC tablets (n = 3), plotted versus t in aqueous media

containing different concentrations of SDS stirred at 100 rpm.

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Influence of SDS on HPMC matrix tablets 503

into Equation (4) and this is consistent with the find-ings of Kavanagh and Corrigan[12] and Tahara et al.[15] As is shown in Table 2, the rate constant (k

1) appeared to

decrease with increased SDS concentrations.In contrast to the diffusion layer, the polymer was

dominant over SDS in the gel layer. SDS concentra-tions in the gel layer are expected to be substantially lower than polymer saturation point (PSP). At low SDS concentrations, the viscosity of the gel layer increased with SDS concentrations.[21] This resulted in a reduc-tion in the penetration of water into the polymer matrix and consequently the rate and extent of tablet swelling. Furthermore, an increase in tablet erosion at high SDS concentrations also contributed to the decrease in water uptake at these SDS concentrations.

Drug solubility

The solubility of NM measured in each of the five media is shown in Table 3 which clearly shows NM solubility increases with increasing SDS concentration in water, and NM solubility in water containing an SDS concen-tration of 1% is the nearly 1000-fold in water. Obviously, all of the SDS concentrations studied are above the SDS CMC concentration, and micelles are formed in water. As a consequence of it, NM becomes incorporated in micelles and NM solubility increases.

Drug release

In order to examine the effects of SDS on the dissolution profiles of a poorly water-soluble drug (NM), dissolu-tion studies were conducted using the aqueous medium

containing an SDS concentration of 0%, 0.3%, 0.5%, 0.8%, 1% (w/v) SDS. The solubility of nimodipine meas-ured in each of the five dissolution media are shown in Table 3. Nimodipine has very limited solubility in aque-ous media due to its low aqueous solubility (e.g., 3.5 g/mL). The solubility of nimodipine in aqueous medium containing an SDS concentration of 0.3%, 0.5%, 0.8%, 1% w/v is sufficiently increased to maintain a sink condition during dissolution test. Figure 5 shows the effects of the various surfactant concentrations on the dissolution profile of nimodipine. The dissolution of nimodipine HPMC tablets in water without added SDS was less than 15% within 15 hours, however, this increased up to 100% when 1% SDS was added to the dissolution medium. The dissolution of nimodipine in media containing 0.3%, 0.5% and 0.8% were approximately 75%, 85% and 94% within 16 h, respectively. These results indicate that the extent of dissolution of nimodipine is significantly dependent on SDS concentrations within the media, and the extent of dissolution of nimodipine increased with the concentration of SDS.

From the results above, it is seen that the influence of SDS on the dissolution of poorly soluble drugs is differ-ent from that on the dissolution of water-soluble drugs. The principal mechanism by which surfactants retard soluble drug release from HPMC matrix tablets is by a drug/surfactant ionic interaction. A water-soluble drug can form poorly water-soluble complexes with sodium alkyl sulphates and the resultant complexes have lower aqueous solubilities than their corresponding par-ent drug, leading to a reduction in its dissolution rate. Conversely, SDS increases the dissolution of a poorly water-soluble due to the combined effect of an increased solubility of the drug and accelerated erosion of HPMC matrix tablets by the surfactant.

The mechanism of drug release from HPMC matrix tablets is complex and not completely understood.

Table 2. The swelling parameters for HPMC tablets in measured in aqueous media containing different concentrations of SDS stirred at 100 rpm.

SDS k1 (h0.5) r2

0% 2.509 0.9925

0.3% 2.372 0.9937

0.5% 2.196 0.9974

0.8% 2.081 0.9896

1.0% 1.880 0.9912

Table 3. The solubility of nimodipine measured in aqueous media containing different concentrations of SDS at 37°C.

SDS

Solubility of nimodipine

(g/mL)

0% 3.5

0.1% 18.8

0.3% 147.6

0.5% 464.6

0.8% 955.5

1.0% 2087.0

0102030405060708090

100110

0 2 4 6 8 10 12 14 16Time (hours)

Dis

solu

tion

rate

(%)

1.0%SDS0.8%SDS0.5%SDS0.3%SDSWater

Figure 5. The release of NM from HPMC tablets in aqueous media containing different concentrations of SDS stirred at 100 rpm.

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Some systems may be classified as either purely diffu-sion or erosion controlled, while most systems exhibit a combination of these mechanisms.[24] In this study, NM release from matrix tablets in aqueous media containing different concentrations of SDS was shown to follow the Korsmeyer-Peppas Equation. As illustrated in Table 4, a correlation coefficient (r2) greater than 0.9869 was obtained in all media when the data were treated using the Korsmeyer-Peppas model. The release mechanism, denoted by the n value, appears to be dependent on both diffusion and erosion.

Cloud point

When the HPLC solution is heated above the lower critical solution temperature, the polymer precipitates, resulting in a cloudy solution. The lower critical solution temperature is cloud point (CP). The clouding manifests a phase separation into one rich-polymer phase and one water phase containing almost no polymer. The former phase could be considered as a hydrated solid.

In Figure 6, the cloud point values are presented for the aqueous media containing 1.0% HPMC and varying SDS concentrations. The CP values of 1.0% w/v HPMC solution were about 65°C, 60°C and 58°C at 0%, 0.1% and 0.3% SDS

concentrations, respectively. However, further increasing SDS concentrations resulted in an increase in the CP such that the cloud point value was 88°C at 0.5% SDS concentra-tion, and at 0.8% and 1.0% SDS concentrations the sample did not display a cloud point, with the cuvette remaining clear until temperature reached 90°C. At low SDS con-centrations, the CP decreased with SDS concentrations whilst at high SDS concentrations, the CP increased with increased concentration of SDS. These results are in agree-ment with those reported previously.[20]

In the water-HPMC system, when an ionic surfactant like SDS was added, the surfactant molecules formed small aggregates with HPMC by an attractive hydrophobic interaction between the polymer and SDS. At low SDS con-centrations, as a consequence of the binding, the HPMC molecules became charged and expanded due to repul-sion between the charged surfactant head groups, leading to decreased cloud points. At higher SDS concentrations, the binding of the surfactant to the polymer was hindered by the repulsions between polymer head-groups, result-ing in a polyelectrolytic system that exhibited an increased cloud points.[20] Similar effects on modified celluloses was also reported and discussed earlier.[22]

Conclusions

The study showed that SDS affected both the swelling and erosion of HPMC matrix tablets in aqueous media. SDS was shown to hinder swelling and increase erosion of HPMC matrix tablets possibly due to the attractive hydrophobic interaction between HPMC–SDS. Study of cloud point of the HPMC gel further supported the hypothesis of this interaction between this surfac-tant and polymer. The study also showed that medium containing SDS can increase the extent of NM release from HPMC matrix tablets, which have been caused by increased NM solubility in the dissolution medium and increased erosion of HPMC matrix tablets.

Acknowledgements

This work was supported in part by a grant (No. 30672551) to Qiang Fu from National Natural Science Foundation of China.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Table 4. The effect of SDS concentrations on the release exponent and regression coefficient from analysis of the release of nimodipine from HPMC tablets.

SDS Conc. (w/v) 0.3% 0.5% 0.8% 1.0%

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