Impact of sodium dodecyl sulphate on the dissolution of poorly soluble drug into biorelevant medium from drug-surfactant discs

International Journal of Pharmaceutics 467 (2014) 1–8

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International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm

Impact of sodium dodecyl sulphate on the dissolution of poorly soluble drug into biorelevant medium from drug-surfactant discs Peter Madelung a , Jesper Østergaard a , Poul Bertelsen b , Erik V. Jørgensen b , Jette Jacobsen a , Anette Müllertz a,∗ a b

Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, Denmark Takeda Pharma A/S, Langebjerg 1, Roskilde, Denmark

a r t i c l e

i n f o

Article history: Received 9 October 2013 Received in revised form 22 February 2014 Accepted 27 February 2014 Available online 2 March 2014 Keywords: Miniaturized rotating disc dissolution Physiologically relevant dissolution Poorly soluble drugs Surfactants in tablets UV–vis fibre optic probes

a b s t r a c t The purpose was to elucidate the mechanism of action of sodium dodecyl sulphate (SDS) on drug dissolution from discs under physiologically relevant conditions. The effect of incorporating SDS (4–30%, w/w) and drug into discs on the dissolution constant and solubility were evaluated for the poorly soluble drugs griseofulvin and felodipine in a biorelevant dissolution medium (BDM). Dissolution constants from dissolution profiles of drug discs with and without SDS were measured using miniaturized rotating disc dissolution. Solid state changes were investigated by X-ray diffraction. Solubility was determined using HPLC-UV. The interaction between micelles in BDM and SDS was investigated by isothermal titration calorimetry and dynamic light scattering. Isothermal titration calorimetry showed that SDS formed mixed micelles with bile salt:phospholipid (BS:PC) micelles in BDM. Dynamic light scattering showed that the addition of SDS made the BS:PC micelles grow up to 2.5 times in volume. As a function of SDS addition, the dissolution constant showed an apparent exponential increase, while drug solubility showed a weak linear dependence. The pronounced effect on dissolution constant with SDS in the discs is not caused by an increased surface area as SDS dissolves, micelles in the bulk medium or changes in the solid state properties of the drugs. The proposed mechanism involves a high local concentration of SDS at the solid–liquid interface as SDS dissolves and this solubilizes the drug. The improved solubility at the solid–liquid interface provided a much steeper concentration gradient resulted in a faster dissolution. The total amount of SDS in the discs only gave a minor increase in total surfactant concentration in the dissolution medium and did therefore not to any large extent affect the drug solubility in the bulk. © 2014 Published by Elsevier B.V.

1. Introduction Poorly soluble drug (BCS class II) (Amidon et al., 1995) commonly have low and variable bioavailability (Schwebel et al., 2011), and for this reason strategies to improved dissolution rate or solubility of these drugs are of interest both in academia and industry. Surfactants are widely used in tablets to improve the wetting and solubilization and thereby the bioavailability of poorly soluble drugs. The addition of surfactant to tablets appears largely to improve the dissolution rate since the amount of surfactant in a

Abbreviations: BDM, biorelevant dissolution medium; BS, bile salt; CMC, critical micelle concentration; DLS, dynamic light scattering; FLP, felodipine; GRF, griseofulvin; IDR, intrinsic dissolution rate; ITC, isothermal titration calorimetry; PC, phosphatidyl choline; SDS, sodium dodecyl sulphate; XRD, X-ray diffraction. ∗ Corresponding author. Tel.: +45 353 36440; fax: +45 353 06031. E-mail address: [email protected] (A. Müllertz). http://dx.doi.org/10.1016/j.ijpharm.2014.02.043 0378-5173/© 2014 Published by Elsevier B.V.

tablet is rarely sufficient to solubilize the dose entirely and once the tablet has disintegrated, the solubility of the drug within the intestinal fluid is increased to a minor degree only (de Waard et al., 2008; Heng et al., 1990; Ruddy et al., 1999; Schott et al., 1982). The surfactants SDS, Polysorbate 80 and Triton X-100 were used in range of 0.2 and 20% (w/w) (de Waard et al., 2008; Heng et al., 1990; Ruddy et al., 1999; Schott et al., 1982). The mechanisms behind the improved bioavailability obtained when surfactants are added to tablets, have been reported to be caused by the ability of the surfactants to induce faster disintegration and produce a finer dispersion of drug particles after disintegration of the tablet, which again will result in higher dissolution rates (Heng et al., 1990; Schott et al., 1982). The disintegration and dissolution in these studies were investigated using pharmacopoeial dissolution apparatus with either basket (Heng et al., 1990; Schott et al., 1982) or paddle stirring (de Waard et al., 2008). Relating the hydrodynamics of the USP I or II to the in vivo situation requires the use of the nondimensional Reynolds number from fluid mechanics. The Reynolds

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number is the ratio of fluid inertia to viscous force around an object, in this case a tablet. The Reynolds number for the bulk flow in the USP I or II is much higher than what is estimated to occur in vivo and the Reynolds number at the interface between the tablet and the bulk medium is estimated to be even smaller than that of the bulk (Diebold, 2005). Disintegration is an intricate part of the currently suggested mechanism for increased bioavailability (de Waard et al., 2008; Heng et al., 1990; Schott et al., 1982), therefore it is important to be able to separate the effects of disintegration and dissolution from tablets, in order to understand the effects of surfactants in tablets. The purpose of the present study was to elucidate the mechanism of action of surfactants added to drug discs under physiologically relevant conditions where the discs did not disintegrate. The effect of incorporating sodium dodecyl sulphate (SDS) into discs containing the poorly soluble drugs griseofulvin (GRF) and felodipine (FLP) were evaluated on the dissolution rate and solubility, under conditions where the discs did not disintegrate. GRF and FLP were selected as model drugs due to their similar molecular weights (352 and 384 g/mol, respectively) and different lipophilicities, since their solubility in medium chain triglycerides is 0.095% (w/w) (Kaukonen et al., 2004) and 3.1% (w/w) (von Corswant et al., 1998) for GRF and FLP, respectively. The discs in this study serve as miniaturized tablet analogues, enabling in vitro studies assumed to reflect the in vivo fasted state. The dissolution rate constant and solubility serve as a means to assess the effect of SDS incorporation in tablets, on the amount of these poorly soluble drugs available for absorption.

equilibration time for the sample cell to stabilize at 37 ◦ C. The obtained data was processed using the Zetasizer Software, version 6.20 (Malvern Instruments Ltd., UK). By an autocorrelation function the software correlates the intensity fluctuations caused by scattered light from moving particles and transforms these fluctuations to diffusion coefficients and a particle size of the equivalent sphere using the Stokes-Einstein’s equation. The mean particle size of the particles in BDM was calculated as a number distribution. 2.3. Solubility The solubility of GRF and FLP in BDM with up to 1 mM SDS was determined by dispersing more than 1 mg/ml of drug for 21 h at 37 ◦ C using end-over-end rotation. Samples (n ≥ 5) were centrifuged for 15 min at 13,000 rpm and 37 ◦ C. The supernatant was diluted 1:1 with acetonitrile (ACN) and centrifuged again. Standards were prepared by the same procedure. The amounts of drug dissolved were determined by HPLC. 2.4. Quantitative analysis Samples for powder uniformity and drug solubility in BDM were analyzed on a Dionex Ultimate 3000 HPLC system. A Phenomenex Luna C18 column (125 ␮m × 4.00 ␮m × 5 ␮m), at 30 ◦ C, a flow rate of 1.5 ml/min and a mobile phase of 70/30 ACN/water (v/v) were used. UV–vis detection was performed at 292 nm and 362 nm for GRF and FLP, respectively. 2.5. Disc characteristics before and after dissolution

2. Materials and methods NaH2 PO4 , SDS (≥98.5%) and Griseofulvin from Penicillium griseofulvum (97.0–102.0%) were purchased from Sigma–Aldrich (Copenhagen, Denmark). FLP was a gift from AstraZeneca in Sweden and phosphatidyl choline (PC) was purchased from Lipoid AG (Ludwigshafen, Germany). NaCl and NaOH were purchased from Merck (Darmstadt, Germany). Crude sodium taurocholate, from ox bile was used as bile salt (BS) (Sigma ID: T0750). The BS contains 90% conjugated cholic acids. The BS content was determined using a total bile acid assay from Diazyme Laboratories (Poway, CA, USA). Sodium taurocholate with a high purity, ≥95%, (Sigma ID: T4009) was used comparatively in dynamic light scattering (DLS). 2.1. Dissolution medium The biorelevant dissolution medium (BDM) simulating the fasted state intestinal fluid consisted of 35 mM phosphate buffer (pH 6.5 and adjusted to an ionic strength of 154 mM with NaCl), 1.25 mM PC and 5 mM BS. 2.2. The effect of adding SDS on the micelles in BDM Demicellization of SDS in buffer and in BDM was measured by isothermal titration calorimetry (ITC) on a VP-ITC (Microcal Inc., Piscataway, US), according to (Beyer et al., 2006; Taheri-Kafrani and Bordbar, 2009). The heating rate, required to maintain a constant temperature difference between the sample cell and a reference cell filled with deionized water, was measured and integration of the heat rate provides the total energy output of the injection. The particle size distribution of the micelles in BDM with the addition of SDS and concentration dependence of SDS on micellar size was determined by DLS. Using a Zetasizer nano ZS Model ZEN 3600 (Malvern Instruments Ltd., UK) equipped with a 532 nm laser and using a MPT-2 autotitrator (Malvern Instruments Ltd., UK). Samples were measured using default back scattering settings measuring at 173◦ , 5.55 mm from the cell wall, no laser attenuation and 10 min

In order to obtain similar particle sizes of the substances being mixed FLP, anhydrous lactose and SDS were ground in a mortar with a pestle for 10 min. GRF was already micronized and was used as received. Light microscopy of the ground powders showed particles sizes for GRF, FLP and SDS were less than 10 ␮m. Powder mixtures of 5–30% (w/w) SDS in GRF and 4–20% (w/w) SDS in FLP were produced by mixing drug and SDS, to give in total 0.5 g, in a mortar with a pestle for 2 min. Using the same approach, the powder mixtures of 30% (w/w) and 25% (w/w) lactose with GRF and FLP, respectively, were prepared. The uniformity of the powder mixtures with SDS were assessed by sampling 5 times from each mixture, dissolving each sample in ACN and quantifying the amount of GRF or FLP in the powder by using UV-HPLC. The composition of selected discs of FLP and SDS were analyzed after the dissolution experiments, by dissolving the remaining disc in ACN, measuring the FLP content and comparing it to the weight of the disc. Discs of powder mixtures were prepared using the mini-IDR compression system (Heath Scientific, Bletchley, UK). Approximately 10 mg of powder mixture were used and the discs of GRF and FLP with added SDS were compressed in the steel dies for 1 min at 30 and 25 bar, respectively. The prepared discs were examined under a light microscope before and after the dissolution experiments. X-ray diffraction (XRD) of the discs before and after dissolution were measured on a X’Pert PRO X-ray diffractometer (PANalytical, Almelo, The Netherlands; MPD ˚ 45 kV; 40 mA) using a PW3040/60 XRD; Cu KR anode;  = 1.541 A; custom made insert where the disc surface was levelled with the height of the aluminium plate ordinarily used for powder reflection measurements on this instrument. The intensity of the reflected xrays was collected using X’Pert Data Collector software (PANalytical B.V.) 2.6. Dissolution Dissolution profiles of discs in BDM were obtained using the ␮DISS Profiler (pION Inc., Woburn, MA, USA), with Teflon disc stirrers and a fiber optic probe (1 cm path length). For each powder

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Fig. 1. Titration of 12.5 mM SDS in buffer where demicellization was endothermic (left) and titration of BDM with BDM including 12.5 mM SDS, which was exothermic (right).

mixture 4 or more repetitions, in 10 mL of BDM at 37 ± 0.5 ◦ C with a constant stirring rate in the range from 50 to 1450 rpm, were used to determine the dissolution behaviour. Concentrations GRF and FLP in the dissolution medium were determined based on standard curves prepared (Fagerberg et al., 2010) using an area-under-the-curve of the second derivative spectral method (Berger et al., 2007; Bijlani et al., 2007; Toher et al., 2003; Bynum et al., 2001). The addition of SDS to the discs did not alter the absorptivity of GRF and FLP in BDM. Dissolution profiles were analyzed using either a single- or biexponential function, which are solutions to the Noyes-Whitney differential equation, as shown in Eq. (1) (Noyes and Whitney, 1897). d[Drug] = kPowder (SPowder − [Drug]) + kDisc (SDisc − [Drug]) dt ⇒ [Drug](t) = SPowder (1 − e

−k

Powder−t

) + SDisc (1 − e

−k

Disc−t

)

(1) In Eq. (1), SPowder and SDisc refers to the contribution from powder or disc to the total solubility, kPowder to the dissolution rate constant of the powder and kDisc to the dissolution rate constant of the disc (Avdeef and Tsinman, 2008; Berger et al., 2007; Tinke et al., 2005). The powder term in Eq. (1) was added to account for loosely packed powder on the disc surface or poor compactability of the substance being compressed (Avdeef and Tsinman, 2008). In Eq. (1) kPowder and kDisc are 1st order rate constants, which are functions of the height of the diffusion boundary layer (h), the diffusion coefficient (D) and area (A) of the dissolving substance and the volume (V) it dissolves in as shown in Eq. (2) (Brunner, 1904; Diebold, 2005; Nernst, 1904). k=

D·A h·V

(2)

In a rotating disc system, h is simply a function of the viscosity of the solution (), the diffusion coefficient of the drug (D) and the rotation speed of the disc (RPM) as shown in Eq. (3) (Avdeef and Tsinman, 2008; Levich, 1962). h = 4.98 · 1/6 · D1/3 · RPM−1/2

(3)

Since some of the discs disintegrated during dissolution, the profiles were analyzed until 50% of the solubility was reached and the constraint that SPowder + SDisc was equal to the solubility determined by UV-HPLC was imposed on Eq. (1). Dissolution profiles were fitted

to Eq. (1) using the OriginPro 8.6 software (OriginLab Corporation, Northampton, MA, USA). Different rotation settings (50–1450 rpm) were used in this study in order to obtain dissolution profiles within a reasonable time interval. Therefore kDisc was normalized according to Eqs. (2) and (3) (kDisc ∝ RPM½ ) (Grijseels et al., 1981; Levich, 1962).

3. Results and discussion 3.1. The effect of adding SDS on the micelles in BDM Demicellization of SDS in buffer and in BDM was measured by ITC, in order to determine whether SDS formed mixed micelles with BS and PC. The endothermic output observed at low surfactant. Fig. 1 (left) is the result of dissociation of surfactant micelles when titrant is added into the measuring cell. This dissociation exposes the apolar surfactant tails to the polar water and this process is endothermic. When the total surfactant concentration in the sample cell exceeds the critical micelle concentration (CMC) dissociation no longer occurs and the endothermic signal approaches a value corresponding to the dilution heat of the micelles (TaheriKafrani and Bordbar, 2009). Demicellization heats and CMC for SDS 224 micelles in buffer are shown in Eqs. (1)–(3). Fig. 1 (left). A CMC value of 1.27 mM, at the current counter ion concentration, was determined as the inflection point, i.e. the negative peak of the first derivative. The CMC value determined, at the counter ion concentration in the buffer and the temperature is in accordance with previous studies (Rosen, 2004a). Titration of BDM containing SDS solution into the BDM was an exothermic process and demicellization of SDS was not observed. Fig. 1 (right). Based on these titrations it can be deduced that SDS micelles are not present in the BDM, suggesting that there is no coexistence of BDM and SDS micelles and that SDS, BS and PC are forming mixed micelles. Fig. 2 shows the particle size of the micelles in BDM as number distribution upon addition of SDS. These micelles represent 100% of the total number of particles. During addition of SDS the micelles in BDM increase 2.5-fold in volume, from a radius of 2.0 ± 0.1 nm with no SDS added to a maximum of 2.8 ± 0.08 nm when 0.789 mM SDS was added to BDM (Tabulated results are included in the supporting information). The BS:PC micelles are smaller than previously reported (Mazer et al., 1980; Schurtenberger et al., 1985). Pure SDS micelles are 2.1 ± 0.08 nm in radii from 3.75 to 25 mM SDS (n = 70),

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Fig. 2. Size distribution by number and scattering intensity (photons/sec) of micelles in BDM. Values are mean ± SD (n ≥ 6).

which is in accordance with previous studies (Mazer et al., 1976; Naskar et al., 2013). When assessing the intensity distribution it was observed that BDM contains both micelles and larger particles. The total amount of these particles was insignificant, but since they are much larger than the micelles, they contributed to the intensity distribution. The particles are an impurity in the crude BS since DLS of BDM containing high purity sodium taurocholate showed only micelles and no larger particles (data not shown). Sodium taurocholate was used since it is the major constituent in the employed BS. In the DLS experiment Rayleigh’s approximation is fulfilled (1 ≫ 2r/), e.g. the radii of the micelles is much smaller than the wavelength of the laser. Therefore, the intensity of the scattered light is proportional to r6 and the increase in micelle radii should give a 7-fold increase in light scattering intensity if the micelle concentration remained the unchanged. However, a less than 2fold increase in light scattering intensity could be observed when 2.5 mM SDS was added to BDM. This shows that the interaction between SDS and BS:PC micelles causes the formation of larger, but fewer mixed SDS:BS:PC micelles.

Fig. 3. Solubility GRF and FLP in BDM (35 mM phosphate, pH 6.5, adjusted to [I] = 154 mM with NaCl, 1.25 mM PC and 5 mM BS) with added SDS, rotated for 21 h at 37 ◦ C. Values are mean ± SD (n ≥ 5).

Drug solubility has previously been measured using the ␮DISS profiler and Eq. (1) used for data analysis (Avdeef and Tsinman, 2008; Berger et al., 2007; Fagerberg et al., 2010; Tsinman et al., 2009). Solubility determination from powder dissolution studies, using Eq. (1), was attempted in this study, but gave a higher solubility, for GRF, as the traditional end-over-end rotation and quantification by UV-HPLC. An overestimated drug solubility, using fiber optic probes, has been shown to be caused by absorption of light by solid drug particles that are less than 500 nm in diameter (Van Eerdenbrugh et al., 2011). The discrepancy in the solubility between powder and disc for GFR is in accordance with previous finding (Avdeef and Tsinman, 2008; Berger et al., 2007; Tsinman et al., 2009). The two methods yielded similar solubilities for FP suggesting that differences in solubility from powder, disc or traditional end-over-end rotation and quantification by UV-HPLC is drug specific. For this reason UV-HPLC was used to determine the solubility of both compounds.

3.2. Solubility

3.3. Disc characteristics before and after dissolution

Fig. 3 shows the solubility of GRF and FLP in BDM with increasing amounts of SDS. A clear linear relationship between GRF and FLP and the concentration of SDS in the BDM was observed in the investigated range. The solubility of both GRF and FLP increased approximately 15% upon addition of 1 mM SDS to BDM, compared to BDM without added SDS. (Tabulated results are included in the supporting information.) The linear dependence in Fig. 3 is in accordance with the effect of surfactants on the solubility of poorly soluble drug (Rosen, 2004b). The increase in drug solubility with increasing SDS concentration in BDM, indicated by the slopes in Fig. 3, is higher for FLP as compared to GRF, which is interpreted as FLP having a higher tendency to partition into the micellar pseudo-phase. This is in accordance with previously reported solubilities of GRF and FLP in BDM of similar composition (Persson et al., 2005; Soderlind et al., 2010). The fact that the micelles are becoming larger and less abundant (Fig. 2), show that the increasing solubility in the medium is caused by the micelles becoming more hydrophobic giving a higher affinity of the drugs for the micelles. Stronger association of solubilizates to micelles is generally observed when the micellar volume is increased (Rosen, 2004b).

The uniformity of the powder mixtures showed RSD values of less than 3% and 5% for GRF and FLP, respectively, which was found suitable for the dissolution experiments. (Tabulated results are included in the supporting information.) Apart from showing that the powder blend was homogeneous, the UV-HPLC method also provided a measure of the drug content of each powder mixture and from this the composition was known. This provided information on the amount of SDS in the discs and the SDS concentration in the medium when all SDS had dissolved from the discs using mass balance considerations. Fig. 4 shows pictures of selected discs before and after dissolution. Prior to dissolution all discs, from powder mixtures, had a smooth surface, but upon exposure to the BDM and during dissolution, uneven surfaces were observed and pore like structures were apparent. Discs of pure drug showed no change in surface area upon exposure to BDM during dissolution overnight. The extent to which the surface morphology changed was depending on the amount of SDS initially present in the disc, larger amounts of SDS led to the most significant changes. Similar changes were observed for the discs containing lactose, which was added to determine the significance of the changes in the surface area. Initially, when determining

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Fig. 4. Pictures from light microscope of GRF discs containing 10% SDS (w/w) before (left) and after dissolution (middle). GRF disc with 30% lactose (w/w) (right) after dissolution. All discs had a diameter of 3 mm.

suitable conditions for preparing the disc it was observed that SDS liquefied at pressures of even a few bars. Liquefied and then resolidified SDS could be observed on the steel die in the periphery of the disc after compression. Tests were conducted to determine the maximum amount of SDS in the powder mixture and the maximum compression force which could be applied without observing any SDS in the periphery of the discs after compression. A maximum of 30% (w/w) SDS in the GRF discs and 20% (w/w) SDS in the FLP discs could be prepared. It was also observed that the rate of increase in compression pressure had an influence on the appearance of liquefied SDS next to the compressed disc. The liquefication of SDS during compression might affect the solid state properties of the drugs. Therefore XRD diffractograms of the discs were obtained before and, when possible, after dissolution. The results are shown in Fig. 5. When comparing the relative peak positions of the drug powder with that of the drug containing discs, no changes were observed. Fig. 5 shows that the solid state properties of GRF and FLP are not changed by compression, upon exposure to BDM during dissolution, and SDS as well as lactose addition. With respect to SDS, comparison of the diffractogram obtained for SDS powder and the SDS containing discs showed that most structural features related to SDS were lost when mixed with drug and compressed into a disc. The upwards sloping baseline and the intense peak appearing at a 2◦  between 21 and 21.5 are caused by the custom made sample holder. The lack of change in the XRD diffractograms suggests that any effect on drug dissolution with SDS incorporation in this study would not be related to any change in the solid state properties of the drugs.

3.4. Dissolution The dissolution of GRF and FLP from pure discs and drug-SDS discs was determined in BDM at 37 ◦ C using the ␮DISS profiler. The incorporation of SDS into the discs significantly altered the dissolution of GRF and FLP (Fig. 6). A faster dissolution of GRF and FLP was observed with increasing SDS percentages in the disc. Dissolution profiles obtained from discs compressed from mixtures of FLP and SDS were adequately described by a single exponential expression yielding no contribution to total solubility from the powder term of Eq. (1). However, some discs containing mixtures of GRF and SDS lead to biexponential dissolution profiles giving an average value for SPowder of 2.5 ␮g/ml and showing no dependence of kPowder on the addition of SDS to the discs. Eq. (1) was fitted to the dissolution profiles and R2 -values greater than 0.985 were achieved for discs of all powder mixtures of GRF and FLP with SDS. The high R2 -values indicate that the mathematical model used fit the experimental data to a high degree. Previously, dissolution of 2-component discs where complexation between the components occur has been described (Higuchi et al., 1965; Shah and Parrott, 1976). The interactions were weak 1:1 complexations between small molecules different from the partitioning of drugs into micelles. Not only is the nature of the interaction different, also the results of this study cannot be analyzed by the use of the 2-component model since it requires knowledge of the diffusion coefficient and saturation concentration of both components and these cannot easily be defined or measured for SDS in this study. Additionally, it is possible that SDS is

Fig. 5. XRD diffractograms of discs with mixtures of GRF (left) and FLP (right) with incorporated SDS and powder of pure GRF, FLP and SDS.

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Fig. 6. Complete dissolution profiles of GRF (upper left) and FLP (upper right) from disc containing SDS in BDM at varying rotation speeds and at 37 ◦ C. Sectional view of early dissolution for GRF (lower left) and for FLP (lower right). Values are mean (n ≥ 4), of several hundred data point averages and for this reason error bars are omitted for clarity.

present in a hexagonal phase on the disc surface judging from the amount added to the discs, the phase diagram of SDS (Kekicheff et al., 1989) and the fact that the aqueous boundary layer (h) on top of the disc has a volume that is less than 1 ␮L. The hexagonal phase of SDS is highly viscous and consists of a network of practically infinitely long cylindrical micelles (Rosen, 2004a). Using polarized light microscopy no hexagonal phase could be observed after addition of 2.5 ␮L buffer on the disc, which was the maximum applicable volume. This absence could be explained by a small amount of hexagonal phase on the disc or that the crystalline drug in the disc also reflects the polarized light making distinction inherently impossible. Fig. 7 shows the increase in kDisc relative to kDisc without SDS for GRF and FLP as a function of the percentage (w/w) of SDS in the discs. (Tabulated results are included in the supporting information.) Interestingly, there is an apparent exponential dependency of kDisc of GRF and FLP on % SDS (w/w) in the discs. The more SDS the discs contained before dissolution, the softer they appeared after dissolution suggesting that the discs were wetted all the way through. When comparing the dry weight of the disc with the FLP content quantified by UV-HPLC, it appears that all SDS dissolves from the disc, since it was not possible to calculate by mass balance, any SDS in the FLP discs (4%, 8% and 12% SDS (w/w) at n = 6) after dissolution, within the experimental uncertainties of the method. Discs of GRF containing 20%, 25% and 30% SDS (w/w), and discs of FLP containing 16% and 20% (w/w) SDS disintegrated completely during dissolution.

The dissolution of pure GRF and FLP discs in BDM containing 1 mM SDS, corresponding to the maximum amount SDS that could be released from discs containing 30% SDS (w/w), was investigated in order to examine the effect of SDS in the medium on drug dissolution rates compared to the SDS containing discs. In BDM containing

Fig. 7. Progression of normalized kDisc for GRF and FLP with % SDS (w/w) in the discs calculated using Eq. (1), from dissolution profiles in Fig. 6. Values are mean ± SD (n ≥ 4).

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1 mM SDS, GRF and FLP showed a 39 and 43% increase in kDisc compared to BDM, respectively. The effect of SDS in the medium on the dissolution rate of pure GFR discs is in accordance with previous studies (Balakrishnan et al., 2004; de Smidt et al., 1987). The effect BDM, of similar composition, on the dissolution rate of GRF and FLP are in accordance with other studies (Avdeef and Tsinman, 2008; Fagerberg et al., 2010; Persson et al., 2005; Soderlind et al., 2010). Dissolution of GRF and FLP from discs containing lactose instead of SDS was measured in order to assess the effect of an increasing surface area observed in Fig. 4, as SDS or lactose dissolved faster than GRF or FLP. GRF discs containing 30% and FLP containing 25% lactose showed a 65 and 60% increase in kDisc , respectively, compared to discs of pure drug. This is in accordance with previous studies of dissolution from discs containing pores where it was found that below a critical value the increased surface within the pores did not contribute to the dissolution even though the diffusion boundary layer was much smaller than the pores (Grijseels and Deblaey, 1981; Grijseels et al., 1983b; Van Der Graaff et al., 1979). The critical pore diameter has also been shown to be dependent on the rotation speed (Grijseels et al., 1983a). Since only a small increase in kDisc was observed in the current study, it is reasonable to assume that the pores shown in Fig. 4 is approximately at the critical value under the current hydrodynamic conditions. The increase in kDisc , for the lactose containing discs and discs of pure drug in BDM containing 1 mM SDS, is less than twofold which is insignificant compared to the effect observed in Fig. 7. This shows that the dramatic increase in dissolution rate observed when SDS was in the discs is neither caused by the solubilizing effect of SDS in the medium or an increased surface area of the disc as SDS gradually dissolves. In the classical dissolution theory, Nernst-Brunner and the hydrodynamic approach of Levich, the drug has to diffuse through a diffusion boundary layer in order to be dissolved. According to Nernst-Brunner a stagnant layer exits on the surface of the dissolving substance where only diffusion is limiting the dissolution process. In work summarized by Levich, only in the immediate vicinity of the solid–liquid interface, where fluid motion is almost absent, should diffusion be taken into account because the height of the diffusion boundary layer is much smaller than according to Nernst-Brunner (Grijseels et al., 1981). According to Levich forced convection from agitation by the stirring motion is the major driving force for dissolution not diffusion. Both approaches assume that the solution at the solid–liquid interface is saturated and the concentration of drug is decreasing with the distance from the surface eventually reaching the value of the bulk (Brunner, 1904; Grijseels et al., 1981; Levich, 1962; Nernst, 1904; Noyes and Whitney, 1897). The height of the diffusion boundary layer is given in Eq. (3) and is depending on the rotation speed, whereas the composition at the solid–liquid interface remain unchanged as long as laminar flow conditions apply, which is the case at all rotation settings in this study (Riddiford, 1966). By this argument the surface properties of the discs with SDS incorporated remain unchanged irrespective of rotation setting thereby justifying the normalization of kDisc from disc of different SDS levels and different rotation setting (Riddiford, 1966). Higher solubility at the solid–liquid interface leads to a faster dissolution. Therefore the increase in kDisc shown in this study is hypothesized to be a result of a higher local concentration of SDS at the solid–liquid interface as SDS dissolves and solubilizes the drug. The improved solubility at the solid–liquid interface is providing a much steeper concentration gradient giving faster dissolution. The total amount of SDS in the discs only gives a minor increase in total surfactant concentration in the dissolution medium and does therefore not to any large extent affect the bulk solubility. The hypothesis of improved solubility at solid–liquid interface is supported by the difference in the effect of SDS in the disc on GRF and FLP dissolution

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since the increase in solubility in buffered SDS solution is much greater for FLP than for GRF when comparing with data from literature (Abrahamsson et al., 1994; Balakrishnan et al., 2004). Fixing kDisc at the value of pure drug disc in BDM and fitting to Eq. (1), shows SDisc increasing relative to SDisc without SDS for GRF and FLP as a function of the percentage (w/w) of SDS in the discs (Tabulated results are included in the supporting information.). The SDisc value could indicate drug solubility in the diffusion boundary layer. The dependence of relative SDisc on the percentage (w/w) of SDS in the discs is exponential and identical to the effect observed in Fig. 7 for kDisc . Fixing kDisc inherently assumes that D, in Eq. (2), is independent of the concentration of SDS in the diffusion boundary which may not be correct since concentrated solution of SDS becomes very viscous. To summarize, the addition of SDS to the disc with drug causes the apparent bulk equilibrium (solubility) to be reached faster, but the change in solubility is small. This suggests that the effect of adding SDS to the disc is on the kinetics of dissolution, not the thermodynamics of solubility. The discs in this study did not disintegrate or was only analyzed until disintegration in contrast to most other previous reports (Heng et al., 1990; Ruddy et al., 1999; Schott et al., 1982), where disintegration was an intricate part of the proposed mechanism. The hydrodynamic condition in these studies was far from what is currently assumed to be physiologically relevant (Diebold, 2005). Therefore, the suggested mechanism of improved solubility at the interface between the tablet and dissolution medium could have an impact under physiological conditions or when disintegration is not occurring. 4. Conclusion SDS interacts with BS:PC micelles in BDM resulting in the formation of mixed micelles. The DLS experiments showed that the addition of 1 mM SDS to BDM makes the micelles grow 2.5 times in volume. When 1 mM SDS was added to the BDM a 15% increase in the solubility of GRF and FLP was found. The minor change in solubility for GRF and FLP was caused by the formation of fewer, but larger and more hydrophobic micelles. Disc dissolution studies of GRF and FLP showed a significant 330-fold and 900-fold increase in kDisc for GRF and FLP, when 30 and 20% (w/w) SDS was added to the discs, respectively, while addition of the same amount of SDS to the BDM affected the solubility to a much lesser extent. The pronounced effect on dissolution of adding SDS to the discs is not caused by an increased surface area as SDS dissolves from the discs or micelles in the bulk medium. XRD showed that the increase in solubility and dissolution is not related to changes in the solid state properties of the drug in the discs, since no change could be observed from compression, SDS addition or dissolution. The addition of SDS causes the apparent solubility of GRF and FLP to be reached faster, but it is not changed significantly. This indicates that incorporation of SDS into the tablet matrix, acts primarily as a means to increase the dissolution rate. The increase in kDisc for GRF and FLP may be an entirely kinetic phenomenon, caused by proximity of SDS to the drugs. The most likely mechanism is that a high local concentration of SDS is present at the solid–liquid interface as SDS dissolves and this solubilizes the drug. The improved solubility at the solid–liquid interface is providing a much steeper concentration gradient giving faster dissolution. The suggested mechanism correlates well with both the classical understanding of dissolution from Nernst-Brunner and the hydrodynamic approach summarized by Levich. Acknowledgements The author would like to thank Takeda Pharma A/S, Denmark, and Drug Research Academy, at the University of Copenhagen, for

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