Lipid-Based Formulations Solidified Via Adsorption onto the Mesoporous Carrier Neusilin® US2:...

RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

Lipid-Based Formulations Solidified Via Adsorption onto theMesoporous Carrier Neusilin R© US2: Effect of Drug Type andFormulation Composition on In Vitro Pharmaceutical Performance

HYWEL D. WILLIAMS,1 MICHIEL VAN SPEYBROECK,2 PATRICK AUGUSTIJNS,2 CHRISTOPHER J. H. PORTER1

1Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia2Drug Delivery and Disposition, KU Leuven, Leuven, Belgium

Received 10 February 2013; revised 18 March 2014; accepted 25 March 2013

Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23970

ABSTRACT: The current study determined the extent to which the desorption of lipid-based formulations (LBFs) from a mesoporousmagnesium aluminometasilicate (Neusilin R©-US2) carrier is governed by drug properties, LBF composition, and LBF-to-adsorbent ratio. Asecondary objective was to evaluate the impact of testing parameters (medium composition, pH, dilution, and agitation) on in vitro LBFperformance. Two self-emulsifying LBFs, with high/low lipid–surfactant ratios were studied in detail using danazol, fenofibrate, cinnarizine,and mefenamic acid as model drugs. A wider range of 38 different danazol-containing LBF were also evaluated, where desorption wasevaluated immediately after preparation and after 1 month of storage. The results revealed that incomplete desorption from Neusilin R©

was a feature of all drugs and LBFs tested. Desorption was insensitive to agitation but increased under conditions where ionizable drugswere charged. In addition, formulations containing a higher proportion (>30%) of hydrophilic surfactant consistently exhibited higherdesorption, and were least susceptible to decreased desorption on storage. In summary, although Neusilin R© is an effective vehicle for LBFsolidification, its use is accompanied by a risk of incomplete desorption of the vehicle from the carrier, irrespective of the drug. LipidFormulation Classification System (LFCS)Type IIIB LBFs comprising higher quantities of hydrophilic surfactants appear to desorb most fromNeusilin R©. C© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm SciKeywords: poorly water-soluble drugs; lipids; self-emulsifying; adsorption; lipid-based formulations; self-emulsifying drug delivery sys-tems; neusilin R©; adsorbents

INTRODUCTION

Concurrent with the realization that an increasing number ofdrugs under development have low-aqueous solubility, effortsto develop new formulation strategies and to better understandthe existing formulation strategies are also increasing.1 Lipid-based formulations (LBFs) represent one such formulationstrategy.2,3 Improvements in drug bioavailability after admin-istration of poorly water-soluble drugs in LBFs are commonlyattributed to avoidance of traditional dissolution processes,4,5

an ability to stimulate lipid digestion and to enrich the gas-trointestinal tract with endogenous solubilizers (bile salts andphospholipids),6,7 the potential to recruit intestinal lymphatictransport processes and to bypass first-pass metabolism,8 and,finally, the opportunity to promote supersaturation and to in-crease thermodynamic activity at the absorptive site.9,10

In recent years, there has been increasing interest in strate-gies that enable the solidification of liquid and semi-solidLBF11,12 to enable the production of free-flowing powders thatmay be transformed into solid compacts and/or powder-filledcapsules.13 A powder-filled capsule may be particularly attrac-

Correspondence to: Christopher J. H. Porter (Telephone: +61-3-9903-9649;Fax: +61-3-9903-9583; E-mail: [email protected])

Hywel D. Williams’ present address is Capsugel Product Development Centre,200 Technology Square, Cambridge, Massachusetts 02139.

Michiel Van Speybroeck’s present address is Formac Pharmaceuticals, GastonGeenslaan 1, Heverlee 3001, Belgium.

This article contains supplementary material available from the authors uponrequest or via the Internet at http://onlinelibrary.wiley.com/.

Journal of Pharmaceutical SciencesC© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association

tive for convenience purposes because additional excipientsmay not be required. However, low powder density may limitcapsule loading to only a few hundred milligrams. On the con-trary, a tableting approach offers the potential to convert a sig-nificant mass of liquid-loaded powder (as much as a gram) intoa single compact,16 but in this case, significant formulation ef-forts may be required to produce robust tablets that show rapidrates of disintegration.

One popular technique for LBF solidification is the adsorp-tion of the LBF directly onto high-surface-area adsorbentssuch as Aerosil R©, Hubersorb R©, Sylysia R©, and Neusilin R©.13–15

Neusilin R© US2, a magnesium alumino metasilicate in granularform, has been most widely investigated for this application,as it has a high absorbent capacity for liquid substances,13,15–17

and good flowability13 and tabletability.17 However, despite theattractiveness of this approach, we have previously shownusing two exemplar self-emulsifying drug delivery systems(SEDDS) that in vitro and in vivo performance can be re-duced when compared with the equivalent liquid SEDDS.15 Amechanism for this performance differential was postulated,and suggested to reflect incomplete desorption of liquid formu-lation components, and therefore, incomplete release of drugfrom the carrier. The subsequent lower concentrations of sol-ubilized drug (typically decreased to ∼65% of maximum) ulti-mately led to decreased drug absorption in vivo.15 These stud-ies were consistent with those of others13,18 underscoring theseemingly broad applicability of this phenomenon to differentdrugs, formulations, and carriers. In contrast, however, otherstudies have reported complete formulation desorption fromsimilar systems.16,19–21 The presence of contradictory reports

Williams et al., JOURNAL OF PHARMACEUTICAL SCIENCES 1

2 RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology

of complete/incomplete LBF desorption from high-surface-areacarriers highlights a relatively limited understanding of thedrivers of in vitro and in vivo performance of solidified LBFarea. To better understand the factors that govern LBF des-orption from high-surface-area carriers, the present study hasexplored the role of drug type (i.e., ionization tendency), dilu-tion, release media type (i.e., composition and pH), formulationtype and storage duration on desorption from the high-surface-area carrier, Neusilin R©. In total, 38 different LBF have beenevaluated, which has, in turn, allowed some key factors thatdetermine the extent of incomplete desorption phenomenon tobe identified.

The data suggest that incomplete desorption is a commonfeature of Neusilin R© US2-based, adsorbed LBF, and is applica-ble to a diverse set of drugs (both neutral and ionizable) andLBFs, with these effects becoming more pronounced on stor-age. The potential benefits of solidifying LBFs using Neusilin R©

should therefore be balanced against the risk that this approachwill decrease the performance relative to equivalent liquid LBF.

MATERIALS AND METHODS

Materials

Neusilin R© US2 was donated by Fuji Chemical Industry Com-pany (Toyama, Japan). Danazol was obtained from Coral DrugsPVT. Ltd. (New Delhi, India). Cinnarizine, fenofibrate, mefe-namic acid, sodium taurodeoxycholate, >97% (NaTDC), soy-bean oil (a long-chain triglyceride), triacetin (a short-chaintriglyceride), and Tween R© 20, 80, 85 (polyethoxylated sorbi-tan ester surfactants) were all obtained from Sigma Chemi-cal Company (St. Louis, Missouri). Captex R© 355 (a medium-chain triglyceride), and Capmul R© MCM EP (a blend of mostlymedium-chain mono- and diglycerides, with some triglyc-erides) were donated by Abitec Corporation (Columbus, Ohio).MaisineTM 35-1 (a blend of mostly long-chain mono- and diglyc-erides, and some triglycerides) was a generous gift from Gatte-fosse (Saint-Priest, France). Cremophor R© EL (polyoxyl 35 castoroil) and Cremophor R© RH40 (polyoxyl 40 hydrogenated castoroil) surfactants were donated by BASF Corporation (Washing-ton, New Jersey). Phosphatidylcholine (Lipoid E PC S, ∼99.2%pure, from egg yolk) was purchased from Lipoid (Lipoid GmbH,Ludwigshafen, Germany). Water was obtained from a Milli-Q purification system (Millipore, Bedford, Massachusetts). Allother chemicals and solvents were of analytical purity or high-performance liquid chromatography (HPLC) grade.

Preparation of the LBFs

Liquid Self-Emulsifying Drug Delivery Systems

Two LBFs termed “IIIA-SEDDS” and “IIIB-SEDDS” accord-ing to their position within the Lipid Formulation Classifica-tion System (LFCS),22 were used throughout this study andconsisted of Captex R©–Capmul R© (2:1) medium-chain lipids andCremophor R© EL in either a high (5:1, i.e., Type IIIA) or low(1:2, i.e., Type IIIB) lipid–surfactant ratio, and ethanol (10%).In a separate formulation screening study (see below), a morediverse range of lipids and surfactants, in 5:1, 2:1, and 1:2 lipid–surfactant ratios was investigated (Table 1).

To prepare the liquid SEDDS (SEDDSliquid) formulations, thelipid excipients and surfactant were weighed into clean glassscrew-top vials at the required composition and ethanol was

Table 1. The General Composition of High-/Medium-/Low-Surfactant Formulations Used in the Formulation Screening Section, All ofWhich Were Subsequently Adsorbed onto Neusilin R© US2

Composition (%, w/w) of Each Component

Lipida Surfactantb Cosolventc

Low-surfactant LBF 75 15 10Medium-surfactant LBF 60 30 10High-surfactant LBF 30 60 10

LBFs containing high surfactant were of either Type II when containingTween R© 85 or IIIB in all other cases. LBFs containing medium and low surfactantwere of either Type II when containing Tween R© 85 or IIIA in all other cases.

aThe lipid component in the formulation screening study consisted either ofshort-chain lipids (triacetin), medium-chain lipids (Captex R© 355–Campul R© MCMEP, 2:1), or long-chain lipids (soybean oil–MaisineTM 35-1, 1:1).

bThe surfactants in the formulation screening study included Cremophor R©

EL, Cremophor R© RH40, Tween R© 20, Tween R© 80, and Tween R© 85.cEthanol.

then added. To manufacture the drug-containing formulations,the ethanol contained 10 mg/mL of drug. This ethanol stocksolution was added to the lipid–surfactant mixture to achievea final ethanol concentration in the formulation of 10% (w/w)and a drug loading of 1 mg/g of liquid LBF, and this loadingapproach ensured the attainment of accurate drug loadings inall of the investigated formulations. The low drug loading wasutilized to circumvent the possibility that drug would precip-itate during the dispersion tests; however, it is important tonote that our previous study reported no dependence betweendrug loading and extent of LBF desorption from Neusilin R©.15

Vials were sealed and vortex-mixed prior to use. Drug con-tent in SEDDSliquid was verified (in triplicate), as describedpreviously.15

Adsorbed SEDDSliquid onto Neusilin R© (SEDDSNeusilin R© )

IIIA/IIIB-SEDDSliquid described above and the LBFs describedin Table 1 were used to prepare corresponding adsorbed formu-lations (SEDDSNeusilin R© ). Neusilin R© was dried at 60◦C for 2 h toremove physically adsorbed water prior to adsorption of LBF.The required mass of SEDDSliquid was pipetted onto Neusilin R©,and this mixture was stirred with a spatula until a homoge-neous, dry-looking powder was obtained. SEDDSNeusilin R© formu-lations consisted of SEDDSliquid and Neusilin R© in a 2:1 ratio.Drug content in the SEDDSNeusilin R© formulations was verified(in triplicate), as described previously.15

Evaluation of SEDDSliquid and SEDDSNeusilin R© by In Vitro Dispersion

Media

In vitro dispersion studies were performed in water, simulatedgastric fluid (SGF; pH 1.2, 0.1 N HCl with 34 mM NaCl, with-out pepsin), and a non-USP variation of simulated intestinalfluid (SIF*; pH 6.5, 150 mM NaCl, 1.4 mM CaCl2·2H2O, 3 mMNaTDC, and 0.75 mM phosphatidylcholine).

Large Volume Dispersion Tests (Minipaddles)

In vitro dispersion studies of SEDDSNeusilin R© and SEDDSliquid

were performed in SGF using a USP dissolution tester (ErwekaDT6, Heusenstamm, Germany) equipped with a minipaddle ap-paratus (Pharmatest, Hainburg, Germany). To provide varyingdegrees of agitation in the test, paddle speeds of 75, 100, and150 rpm were used. In each experiment, the dispersion testcommenced on addition of 1.5 g of the SEDDSNeusilin R© or 1 g

Williams et al., JOURNAL OF PHARMACEUTICAL SCIENCES DOI 10.1002/jps.23970

RESEARCH ARTICLE – Pharmaceutics, Drug Delivery and Pharmaceutical Technology 3

of the SEDDSliquid to 250 mL dispersion medium (37◦C). Thelarger mass of SEDDSNeusilin R© ensured that the mass of liquidformulation components was the same in both solidified andliquid formulations. Samples (1 mL) removed periodically overa 4-h period were processed as described in the HPLC Detectionof Model Drugs section below to determine the concentration ofsolubilized drug.

Small Volume Dispersion Tests (Test Tubes)

In vitro dispersion studies of SEDDSNeusilin R© and SEDDSliquid

were also performed in smaller 7 mL tests to allow the dis-persion properties of the LBFs to be assessed at lower dilutions(this was not practical using the larger volumes in the minipad-dle apparatus). The dilutions investigated in the test-tube testswere 1 in 20, 30, 50, 70, 80, and 100. For example, to achieve a1 in 50 dilution, 0.225 g of SEDDSNeusilin R© (equivalent to 0.15 gof liquid LBF) was added to 10 mL propylene test tubes, fol-lowed by 7 mL medium (water/SGF/SIF*). After addition of themedium, the tubes were gently mixed and incubated at 37◦Cwith periodic mixing at intervals. Samples (1 mL) removed at2 and 4 h were processed as described in the HPLC Detectionof Model Drugs section below to determine the concentrationof solubilized drug. Tests were also performed using 0.042 gof SEDDSNeusilin R© in 7 mL of dispersion medium for a 1 in 250dilution to determine whether similar results could be attainedusing the large volume minipaddle test and the small volumetest-tube test.

Collection and Separation of Samples Removed During DispersionTests

The measured outcome of the in vitro dispersion experimentswas the concentration of solubilized drug in the dispersed aque-ous phase. This concentration was expressed as a percentage ofthe quantity of drug present in SEDDSliquid and SEDDSNeusilin R©

(i.e., dose), which was directly measured as described below inthe HPLC Detection of Model Drugs section. Samples (1 mL)removed from the dispersion tests were promptly centrifuged(21,100g; Fresco 21 Heraeus R©; Thermo Scientific, Langensel-bold, Germany) at 37◦C for 5 min to sediment the Neusilin R©

particles. In instances where the supernatant was homogenous,an aliquot (100–200 :L) was removed and further diluted withmethanol prior to analysis by HPLC. In instances where thesupernatant contained a poorly dispersed oily phase and aque-ous phase (this was most common when the lipid content in theLBF was high), these phases were removed by pipette (takingcare not to transfer any of the Neusilin R© sediment) to a freshsample tube. The tube was vortex-mixed to fully redisperse theoil phase, and an aliquot (100–200 :L) was removed and furtherdiluted with solvent prior to analysis by HPLC. To allow directcomparison, samples removed during the dispersion testing ofSEDDSliquid and SEDDSNeusilin R© were separated and diluted inthe same manner.

Formulation Screening Study

The composition of the different liquid LBF that were adsorbedonto Neusilin R© in the screening study is shown in Table 1. A to-tal of 38 formulations, containing different chain length lipids,different surfactants, and different lipid–surfactant ratios andloaded with danazol (at a constant 1 mg/g drug loading) wereinvestigated. In this formulation screening study, a slight vari-ation of the small volume dispersion method (described above)

was used. In short, 0.13 g of the different SEDDSNeusilin R© formu-lations were dispersed in 7 mL SIF*. Mixtures were incubatedfor 4 h at 37◦C, after which 2 × 1 mL samples were processedas described above prior to analysis by HPLC. An additional1 mL sample was removed from the dispersion and mixed with4 mL methanol (to dissolve all of the dispersed drug and drugremaining on the Neusilin R© carrier) and processed separately.The concentrations of solubilized drug were expressed as apercentage of the drug concentration measured in this lattersample.

HPLC Detection of Model Drugs

High-performance liquid chromatography analyses for dana-zol, fenofibrate, and mefenamic acid were conducted using aWaters Alliance 2695 Separation Module (Waters Alliance In-struments, Milford, Massachusetts) with a reverse-phase C18

column (150 × 15 mm2, 5 :m; Waters Symmetry R©) protected bya C18 security guard cartridge (4 × 2.0 mm2; Phenomenex, Tor-rence, California). The injection volume was 50 :L and mobilephase flow rate was 1 mL/min. For danazol, the mobile phaseconsisted of methanol and water in a 75:25 (v/v) ratio, andUV detection was at 286 nm. For fenofibrate and mefenamicacid, the mobile phase consisted of acetonitrile and water in a80:20 (v/v) ratio with 0.1% formic acid, and UV detection wasat 288 nm (for fenofibrate) and 280 nm (for mefenamic acid).HPLC analyses for cinnarizine were conducted using a Waters610 fluid unit with a Waters 717 autosampler, Model 600 fluidcontroller (Waters Alliance Instruments), and RF-10A XL flu-orescence detector (Shimadzu Corporation, Kyoto, Japan). Thecolumn was a reverse-phase C18 (150 × 3.9 mm2, 5 :m; WatersSymmetry R©) with a Brownlee reverse-phase guard cartridge(15 × 3 mm2, 7 :m; Alltech Associates, Deerfield, Illinois).The mobile phase consisted of acetonitrile and 20 mM ammo-nium dihydrogen phosphate, pumped through the column ata 1 mL/min flow rate, with detection by fluorescence using anexcitation wavelength of 249 nm and detection wavelength of311 nm.

Nitrogen Physisorption

Nitrogen adsorption–desorption isotherms were recorded usinga Micromeritics TriStar II (Norcross, Georgia) at a temperatureof −196◦C. Blank (i.e., LBF free) Neusilin R© was pretreated at150◦C for 16 h under nitrogen flow prior to analysis to removephysically adsorbed water. LBF-loaded samples were similarlypretreated but at a temperature of 30◦C. The total surface areawas calculated using the Brunauer–Emmett–Teller model. Thetotal pore volume was directly derived from the adsorptionisotherm at P/P0 = 0.95. The pore size distribution was cal-culated from the desorption branches of the isotherm using theBarrett–Joyner–Halenda model.

Statistical Analysis

Statistical analyses were performed using unpaired t-tests orone-way ANOVA tests (followed by Tukey’s test for multiplecomparisons in the latter) using Graph Pad Prism R© 6 for Win-dows (San Diego, California) on log-transformed data (to ob-tain a normal distribution in the datasets). p values lower than0.05 were considered significant.

DOI 10.1002/jps.23970 Williams et al., JOURNAL OF PHARMACEUTICAL SCIENCES


RESULTS

Effect of In Vitro Test Variables on LBF Desorption From Neusilin R©

The impacts of (1) agitation, (2) LBF dilution, and (3) mediatype on the in vitro dispersion performance of LBFs adsorbed toNeusilin R© are presented in Figures 1–3, respectively. The LBFsinvestigated in this section were the IIIA-SEDDS and IIIB-SEDDS formulations shown in Table 1, and contained danazolat a 1-mg/g loading.

The IIIB-SEDDSliquid formulation dispersed rapidly in SGFusing a paddle speed of 100 rpm and maintained all of theincorporated danazol in a solubilized form over the 4-h test du-ration (Fig. 1). The lack of drug precipitation can be explainedby the low danazol loading in the LBF, and therefore, the at-tainment of maximum aqueous phase drug concentrations thatwere deliberately low (i.e., 4 :g/mL) and insufficient to generatesupersaturation and drug precipitation. Under comparable ex-perimental conditions, the equivalent IIIB-SEDDSNeusilin R© for-mulation desorbed significantly less drug (p < 0.05, unpairedt-test), solubilizing only approximately 75% of the dose. Theinability to reach 100% drug solubilization upon dispersion ofSEDDSNeusilin R© has been observed previously15 and, in short,reflects the incomplete desorption of the liquid LBF from theNeusilin R© carrier (this phenomenon is further discussed in theDiscussion section) rather than drug readsorption on the car-rier because the addition of Neusilin R© to a dispersed liquid LBFdid not result in lower solubilized drug concentrations.15 Theperformance of IIIB-SEDDSNeusilin R© formulation with paddlesrotating at 75, 100, and 150 rpm were consistent after 1 h, in-dicating that LBF desorption from the carrier Neusilin R© wasindependent of the mixing conditions within the test.

Figure 2 shows the effect of dilution on the percent of thedanazol dose solubilized in SGF after 4 h dispersion, withthe data for the IIIB-SEDDSliquid and the IIIB-SEDDSNeusilin R©

formulations tested using the minipaddles reproduced fromFigure 1. The rotating minipaddles provided continuous mix-

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Figure 1. Percent danazol dose solubilized during the in vitro disper-sion of SEDDSliquid and SEDDSNeusilin R© in SGF using different paddlespeeds. One gram of IIIB-SEDDSliquid or 1.5 g IIIB-SEDDSNeusilin R©

(providing 1 g of liquid LBF) was dispersed in 250 mL SGF with therotating minipaddles at 75–150 rpm. The formulation used was theIIIB-SEDDS (see Table 1). Danazol loading in the formulations wasconstant (at 1 mg/g liquid LBF). Values are expressed as means (n = 3)± 1 SD.

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Figure 2. Effect of LBF dilution on the percent danazol solubilizedafter 4 h in vitro dispersion of IIIB-SEDDSNeusilin R© in SGF. The dilutionfactors for the liquid LBF component of SEDDSNeusilin R© are shown. Theformulation used was the IIIB-SEDDS (see Table 1). Danazol loading inthe formulations was constant (at 1 mg/g liquid LBF). Performance of1 g IIIB-SEDDSliquid in 250 mL SGF with paddles at 100 rpm(taken from Fig. 1) is shown as a reference. The performance of IIIB-SEDDSliquid and IIIB-SEDDSNeusilin R© in minipaddle dispersion testswas statistically different (p < 0.05, unpaired t-test on log-transformeddata).

ing throughout the duration of the test (blue/red bars in Fig. 2),whereas mixing in the test-tube method (green in Fig. 2) wasonly intermittent. However, there was no evidence that thisdifference in mixing had a significant effect on LBF desorp-tion from Neusilin R© as at a constant 1 in 250 LBF dilution the

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Figure 3. Percent dose solubilized following dispersion of IIIA/IIIBSEDDSNeusilin R© in water, SGF, or SIF*. Bars represent the extent ofdanazol desorption (expressed as a percentage of the total dose) after4 h. The composition of the formulations are shown in Table 1. Danazolloading in the formulations was constant at 1 mg/g liquid LBF. Valuesare expressed as means (n = 3) ± 1 SD. At 4 h, desorption of the danazoldose from IIIA-SEDDSNeusilin R© in SGF was significantly greater thanin SIF* (p < 0.05, one-way ANOVA test with Tukey post-hoc test onlog-transformed data).



percent dose solubilized was 74.4% and 71.1% for the mini-paddle experiments and the test-tube experiment, respectively.The lack of dependency between desorption and mixing is con-sistent with the results shown in Figure 1. It also confirms thatdown-scaling the experiments to test-tube tests did not affectthe level of desorption from Neusilin R©. This was important in apractical sense as the small-scale tests allowed LBF desorptionto be assessed at low dilutions without requiring the use of highquantities of formulation.

The effect of dilution on the desorption of IIIB-SEDDS fromNeusilin R© is also shown in Figure 2. Decreasing dilution from 1in 250 to 1 in 100 and 1 in 80 led to a modest increase in the per-cent dose recovered in the dispersed phase. Further decreasesin dilution had no additional effect on desorption, and in alldilutions investigated, a fraction of the drug (>15%) remainedadsorbed onto the Neusilin R©. A 1 in 80 dilution is consistentwith the dilution factor utilized in previous work,15 and wasused throughout the remainder of the present study.

Figure 3 shows the percent danazol dose in the dis-persed aqueous phase following 4 h dispersion of the IIIB-SEDDSNeusilin R© and IIIA-SEDDSNeusilin R© formulation in water,SGF, and SIF*. The results indicate that LBF desorption wasincomplete irrespective of the media type. In the case of IIIB-SEDDSNeusilin R© , desorption extent was largely consistent acrossthe different dispersion media. Greater desorption from IIIA-SEDDSNeusilin R© was evident in SGF compared with SIF* (p <

0.05, one-way ANOVA). Additional dispersion experiments con-ducted in SIF* containing a range of bile salt–phospholipidconcentrations (see Supporting Information) revealed that thepresence of these solubilizers promoted desorption of both IIIB-SEDDSNeusilin R© and IIIA-SEDDSNeusilin R© formulations, althoughdesorption remained incomplete up to 20 mM bile salt. Thegreater desorption of IIIA-SEDDSNeusilin R© in SGF comparedwith SIF* may therefore be because of pH differences (SGF= pH 1.2, SIF* = pH 6.5), which appears also to have beenattenuated by the presence of bile salts and phospholipids.

Also evident in Figure 3 is the fact that desorption is muchlower in the case of IIIA-SEDDSNeusilin R© compared with IIIB-SEDDSNeusilin R© . The relationship between LBF composition anddesorption behavior is further studied in the FormulationScreening Study section.

In separate tests, the desorption of IIIA-SEDDS formula-tion was assessed following 4 h dispersion in SGF/SIF* andafter transferring the Neusilin R© material (containing residualadsorbed formulation) to fresh SIF*, after an additional 4 h inthis medium. These tests were performed to determine whetherre-establishing sink conditions could promote further LBF des-orption. After the initial 4 h of dispersion, more than 50% ofthe loaded danazol remained adsorbed to the carrier (Fig. 4).The amount of danazol that desorbed once transferred to freshmedium was less than 10% in both tests. It is therefore evidentthat transfer to fresh medium did not facilitate desorption ofthe formulation.

Desorption of Danazol, Fenofibrate, Cinnarizine, and MefenamicAcid Containing LBFs from SEDDSNeusilin R©

Figure 5 compares the extent of desorption of IIIB-SEDDSNeusilin R© (Fig. 5a) and IIIA-SEDDSNeusilin R© (Fig. 5b) con-taining danazol, fenofibrate, cinnarizine, and mefenamic acidfollowing dispersion in SGF and SIF*. Danazol and fenofibrateare both neutral compounds exhibiting low solubility in sim-

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Figure 4. Percent dose solubilized following dispersion of IIIA-SEDDSNeusilin R© following 4 h in SGF or SIF* followed by an additional4 h in fresh SIF*. Bars represent the extent of danazol desorption(expressed as a percentage of the total dose). The composition of theIIIA-SEDDS formulation is shown in Table 1. Danazol loading in theformulations was constant at 1 mg/g liquid LBF. Values are expressedas means (n = 3) ± SD.

ulated gastric23,24 and intestinal fluids (<10 :g/mL). In thecase of the IIIB-SEDDSNeusilin R© formulation (Fig. 5a), the extentof danazol and fenofibrate desorption was largely consistentin SGF (77.6%–80.5%) and in SIF* (79.6%–83.9%). There wasgreater desorption of cinnarizine in SGF (94.7%) than in SIF*(84.2%). Desorption of mefenamic acid was 87.1% and 84.0%in SGF and SIF*, respectively. Using the hydrophilic IIIB-SEDDSNeusilin R© formulation, desorption was generally more effi-cient, and drug and media independent (statistical differenceswere only observed between danazol SGF/SIF* and cinnarizineSGF/SIF* results), but it was not possible to achieve completedesorption.

In the case of the IIIA-SEDDSNeusilin R© formulation (Fig. 5b),desorption was low, varied greatly with drug type, and, withthe exception of mefenamic acid, was dependent on media type.Both danazol and fenofibrate exhibited statistically higher des-orption in SGF than in SIF*. There was some evidence ofgreater danazol desorption in SIF* compared with fenofibrate;however, despite being statistically significant, this effect wassmall. Both danazol and fenofibrate showed lower desorptionin SIF* compared with SGF. Cinnarizine desorption in SIF*was low and comparable to that of danazol and fenofibrate (i.e.,<40%), but was statistically much higher in SGF. The percent ofmefenamic acid desorbed from the IIIA-SEDDSNeusilin R© formu-lation in SGF and SIF* was not statistically different at 63.4%and 65.7%, respectively, and therefore, in contrast to the trendtoward lower desorption in SIF* for the other drugs. Indeed, ofall the drugs investigated, mefenamic acid showed desorptionproperties that were least dependent on the medium used. Incontrast, desorption of cinnarizine was the most dependent onthe medium, showing much greater desorption in SGF.

The results overall suggest that desorption of a drug con-taining LBF from Neusilin R© can be dependent on drug prop-erties, and in particular, the charge status of the drug rel-ative to that of the carrier (described in more detail in theDiscussion section). However, the lack of complete (i.e., 100%)drug solubilization in any condition suggests that incomplete



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ubili

zed

dose

inth

edi

sper

sion

med

ium

afte

r4

h(%

)

Figure 5. Percent dose solubilized following 4 h in vitro dispersionof (a) IIIB-SEDDSNeusilin R© and (b) IIIA-SEDDSNeusilin R© containing dif-ferent drugs in SGF and SIF*. Bars represent the extent of drug des-orption (expressed as a percentage of the total dose) after 4 h. SeeTable 1 for the composition of these formulations. The drug loadingin all formulations was constant at 1 mg/g. Values are expressed asmeans (n = 3) ± SD. Statistically significant differences in SGF–SIF*desorption (p < 0.05, unpaired t-test on log-transformed data): IIIB-SEDDSNeusilin R© (a)—SGF > SIF* in the case of danazol and cinnar-izine; IIIA-SEDDSNeusilin R© (b)—SGF > SIF* in the case of danazol,fenofibrate, and cinnarizine. Statistically significant differences in des-orption of different drugs (p < 0.05 ANOVA plus Tukey post-hoc test onlog-transformed data): IIIB-SEDDSNeusilin R© (a)—SGF, no statistical dif-ferences; SIF*, no statistical differences. IIIA-SEDDSNeusilin R© (b): SGF,cinnarizine > danazol, fenofibrate, and mefenamic acid; mefenamicacid > danazol and fenofibrate, fenofibrate > danazol; SIF*, mefenamicacid > danazol, fenofibrate, and cinnarizine; danazol > fenofibrate, cin-narizine; fenofibrate > cinnarizine.

desorption of LBFs from Neusilin R© is applicable for both neutraland ionizable compounds.

Effect of LBF–Neusilin R© Ratio on Desorption

Results in Figure 6 show the effect of changing LBF–Neusilin R©

ratio on the extent of danazol desorption from IIIB-SEDDSand IIIA-SEDDS formulations (Figs. 6a and 6b, respectively).With increasing proportions of Neusilin R© (i.e., decreasing LBF–Neusilin R© ratios), there is an increase in the mass of LBF inthe mixture that is associated with the carrier. As evident from

a

b

SGF SIF0

25

50

75

1002:1 1:1

Dispersion medium

Dos

e so

lubi

lized

(%

)D

ose

solu

biliz

ed (

%)

1:2

LBF–Neusilin®

LBF–Neusilin®

SGF SIF0

25

50

75

100

Dispersion medium

2:1 1:1 1:2

Figure 6. Percent danazol dose solubilized following dispersion of(a) IIIA-SEDDSNeusilin R© and (b) IIIB-SEDDSNeusilin R© in SGF and SIF*with varying SEDDS–Neusilin R© ratio. Results are expressed as means(n = 3) ± 1 SD. Statistically significant differences in desorption (p <

0.05 ANOVA plus Tukey post-hoc test on log-transformed data): IIIB-SEDDSNeusilin R© (a)—SGF = 2:1 LBF–Neusilin R© > 1:2 LBF–Neusilin R©,1:1 LBF–Neusilin R© > 1:2 LBF–Neusilin R© SIF* = 2:1 LBF–Neusilin R©

> 1:2 LBF–Neusilin R©, 1:1 LBF–Neusilin R© > 1:2 LBF–Neusilin R© IIIA-SEDDSNeusilin R© ; (b)—SGF = 2:1 LBF–Neusilin R© > 1:2 LBF–Neusilin R©,1:1 LBF–Neusilin R© > 1:2 LBF–Neusilin R©, SIF* = 2:1 LBF–Neusilin R© >

1:1 and 1:2 LBF–Neusilin R©, 1:1 LBF–Neusilin R© > 1:2 LBF–Neusilin R©.

Figure 6, this increase in the fraction of LBF associated withthe carrier occurs in parallel with a decrease in the extent ofLBF desorption. This effect was also most pronounced for theIIIA-SEDDS formulations when compared with the more hy-drophilic IIIB-SEDDS formulation. A 2:1 LBF–Neusilin R© ratiogave the highest desorption for the IIIA-SEDDS. This ratio alsoallows the highest formulation loading and as a consequencewas utilized in the Formulation Screening Study section de-scribed below.

The pore size distribution, pore volume, and surface areaof mesoporous materials such as Neusilin R© can be measured



LBF loading (%)

To

talp

ore

volu

me

(cm3

g)

0 20 40 60 80 1000.0

0.2

0.4

0.6

0.8

1.0

1.2 LBF-free Neusilin

1:2 LBF–Neusilin

1:1 LBF–Neusilin

2:1 LBF–Neusilin

bPore diameter (nm)

dV

/dD

(cm3 S

TP

/gn

m)

10 20 30 40 500.00

0.02

0.04

0.06

0.08

LBF–Neusilin 2:1

LBF–Neusilin 1:1

LBF–Neusilin®

®

®

®

®

®

®

®

1:2

LBF-free Neusilin

a/

Figure 7. Nitrogen porosimetry data for LBF-free Neusilin R© andLBF–Neusilin R© systems. (a) Pore size distribution. (b) Total pore vol-ume plotted versus LBF loading. The formulation used for these exper-iments was the IIIA-SEDDS (n = 1).

by nitrogen physisorption.25 The effect of LBF adsorption onthe porosity of Neusilin R© is illustrated in Figure 7. The data inFigure 7a indicate that increased LBF loadings result in a shiftin the pore size distribution toward a larger pore size, sug-gesting that the adsorbed LBF preferentially filled the morenarrow pores. The data in Figure 7b show the total pore vol-ume of Neusilin R© alone and the adsorbed LBF. It is apparentthat the pore volume decreases concurrently with increasedLBF loading. At a 2:1 LBF–Neusilin R© loading, the pore volume

approximates 0 cm3/g, suggesting complete pore filling, and po-tentially overfilling, of the Neusilin R© mesopore system.

Formulation Screening Study

The formulation screening study evaluated 38 formula-tions, comprising either short-chain (triacetin), medium-chain(Captex R© 355:Capmul R© MCM EP, 2:1), or long-chain (soybeanoil:MaisineTM 35–1, 1:1) triglyceride mixed in three differentratios (shown in Table 1) with five different surfactants thatincluded Tween R© 85, Tween R© 80, Tween R© 20, Cremophor R© EL,and Cremophor R© RH40. All formulations contained 10% (w/w)ethanol. Consistent with all experiments in this study, danazolwas incorporated in the LBF at 1 mg/g loading, such that theconcentrations generated on dispersion (∼12.5 :g/mL) were toolow to induce supersaturation and possible precipitation (allow-ing easier interpretation of the desorption data).

The percent danazol desorbed from each formulation follow-ing 4-h dispersion in SIF* is shown in Figure 8. The resultsshow first that danazol desorption was incomplete across all ofthe 38 formulations. It is also evident that the extent of desorp-tion is highly formulation dependent. The systematic mannerin which LBFs were constructed and later tested in this screen-ing study allowed trends in desorption to be related to specificaspects of the formulation, including lipid chain length, natureof the surfactant and lipid–surfactant ratio, and are describedin detail in the following subsections.

Effect of Lipid Chain Length on LBF Desorption

The effect of lipid chain length in the LBF on the extent of dana-zol desorption from the formulations solidified on Neusilin R©

shown in Figure 8 is summarized in Figure 9a, with eachindividual result assigned to its corresponding lipid chainlength category. The horizontal line represents the mean re-sult within each dataset. Although there were some variationin the datasets, there was evidence of greater desorption ofLBF containing shorter-chain lipids. For example, the extentof danazol desorption from a LBF containing 75% short-chainlipid and 15% surfactant (Tween R© 80) was 78.4% compared with45.6% and 54.5% for equivalent medium-chain and long-chainlipid formulations, respectively. At a lower lipid concentration(30%), desorption of the short-chain LBF was almost complete(94.5%), whereas more than 20% drug remained adsorbed inthe case of the medium-chain and long-chain equivalents. The

15% 30% 60%0

25

50

75

100

Sol

ubili

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dose

afte

r4

hdi

sper

sion

(%)

Surfactant in long-chainlipid LBFs

15% 30% 60%

Surfactant in medium-chainlipid LBFs

15% 30% 60%

Surfactant in short-chainlipid LBFs

Tween 85 Tween 80 Tween 20 Cremophor EL Cremophor RH40

(%) (%) (%)

Figure 8. Plot summarizing the effect of increasing the proportion of different nonionic surfactants in LBFs consisting of long-, medium-, andshort-chain lipids on desorption behavior from Neusilin R©. Bars represent the extent of danazol desorption (expressed as a percentage of the totaldose) after 4 h dispersion in SIF*. Long-chain lipids: soybean oil–MaisineTM 35-1 (1:1), medium-chain lipids: Captex R© 355–Capmul R© MCM EP(2:1), short-chain lipids: triacetin (n = 1).



15% 30% 60%0

25

50

75

100

T85 T80 T20 CrEL CrRH400

25

50

75

100LFCSType II

LFCS Type IIIA/B

Long chain Medium chain Short chain0

25

50

75

100

Sol

ubili

zed

dose

afte

r4

hdi

sper

sion

(%)

a b

c

Figure 9. Individual scatter charts summarizing the results of the formulation screening study presented in Figure 8. Graphs plot thepercentage of danazol in solution with respect to (a) the effect of lipid chain length, (b) surfactant concentration, and (c) surfactant type andLFCS classification of the LBFs. Long-chain lipids: soybean oil–MaisineTM 35-1 (1:1), medium-chain lipids: Captex R© 355–Capmul R© MCM EP(2:1), short-chain lipids: triacetin. T85, Tween R© 85; T80, Tween R© 80; T20, Tween R© 20; CrEL, Cremophor R© EL; CrRH40, Cremophor R© RH40. Thehorizontal lines in the plots represent the mean of the categories shown.

performance of the long-chain lipid LBF was slightly betterthan the equivalent medium-chain lipid LBF, showing on av-erage slightly higher desorption percent values; however, thedifferences were small.

Effect of Surfactant Concentration and Surfactant Type on LBFDesorption

The effect of surfactant concentration and surfactant type inthe LBF on the extent of desorption from Neusilin R© shown inFigure 8 are reproduced in Figures 9b and 9c, respectively. In-creasing surfactant concentration led to a progressive increasein desorption. Importantly, this positive effect of increasing sur-factant on desorption was evident across short-chain, medium-chain, and long-chain lipid chain lengths and for each of thesurfactants. Desorption was lowest in the case of Tween R© 85(HLB = 11)-containing LBFs, which are Type II LBFs accord-ing to the LFCS classification.22 Use of the more hydrophilicsurfactants (creating Type IIIA or IIIB LFCS formulations) ledto greater desorption; however, the desorption of LBFs contain-ing Tween R© 20 (HLB = 16.7) and Tween R© 80 (HLB = 15.0)surfactants (that vary only in the alkyl chain length of the sur-factant) were similar. LBFs containing Cremophor R© EL (HLB= 12–14) and RH40 (HLB = 14–16) also demonstrated simi-lar desorption properties. Notably, the desorption properties ofCremophor R© surfactants was on average slightly higher thandesorption from equivalent formulations containing Tween R© 20and 80 surfactants (Fig. 8), particularly at the higher surfac-tant concentrations (i.e., moving from Type IIIA to IIIB for-mulations up to 60% surfactant), but differences between high

HLB surfactants (HLB > 11) are less apparent when the entiresurfactant concentration ranges are considered (Fig. 9c).

Effect of Short-Term Storage on Desorption Properties ofSEDDSNeusilin R©

The desorption performance of the 38 LBFs investigated inthe formulation screening study (described above) was re-evaluated following a period of 1-month storage at elevatedtemperature (37◦C). Formulations were stored in closed vialsto minimize any possible water adsorption or evaporation ofethanol. The results of these tests are shown in Figure 10 andare plotted as the difference in desorption measured follow-ing 1-month storage relative to the results obtained followinginitial assessment (i.e., the results in Fig. 8). Bars below the x-axis therefore reflect incidences where the extent of desorptionof the LBF decreased on storage. The results overall show thatgreater change in the performance occurred in LBFs contain-ing (1) the least amount of surfactant, (2) the more lipophilicTween R© 85 surfactant, and (3) medium-chain lipids. Notably,these examples where storage had the greatest capacity to alterdesorption of the LBF were (perhaps unsurprisingly) stronglycorrelated to LBFs showing comparatively poor desorption inthe first instance.

DISCUSSION

Although several studies have shown that adsorbed LBFscan increase the oral bioavailability of poorly water-solubledrugs,26–28 a previous study has shown that these adsorbedLBFs may still underperform relative to their liquid variants.15



15% 30% 60%

−80

−60

−40

−20

0

20

(%) (%) (%) Surfactant in long-chain

lipid LBFsD

iffer

ence

inda

nazo

ldes

orpt

ion

follo

win

g1-

mon

thst

orag

e(%

)15% 30% 60%

surfactant in medium-chainlipid LBFs

15% 30% 60%

Surfactant in short-chainlipid LBFs

Tween 85 Tween 80 Tween 20 Cremophor EL Cremophor RH40

Figure 10. The extent of danazol desorption from the formulations following 1-month storage time relative to respective initial performance.Negative values indicate a decrease in the danazol desorption following storage. Because of an analytical error, the result for the LC lipidformulation containing 15% Cremophor R© EL is missing from this dataset (n = 1).

The aim of the present study was to determine whether thisphenomenon of incomplete desorption of LBF from a meso-porous adsorbent (Neusilin R©) is a general effect that is applica-ble to a range of different drugs and LBF compositions and dif-ferent simulated gastrointestinal conditions. The results showthat incomplete LBF desorption from Neusilin R© occurs for neu-tral, basic, and acidic drugs, and for a number of different for-mulations under a broad range of physiologically relevant testconditions. Importantly, however, LBF types that are most re-sistant to these problems and that show robust desorption fromNeusilin R© (>80%) are also identified.

In Vitro Mixing Conditions Do Not Greatly Influence LBFDesorption from Neusilin R©

A range of in vitro dispersion tests were utilized in the presentstudy to assess the extent of LBF desorption from Neusilin R©.This approach was considered valid based on our previouswork15 that showed that the in vivo performance of liquid andadsorbed SEDDS was predicted by the extent of drug solubi-lization in simple dispersion tests. It should be noted that inthese previous studies (and here), drug loadings throughoutthis study were intentionally kept low (1 mg/g) to eliminate therisk of drug precipitation and to allow evidence of incompletedrug recoveries in the dispersion experiments to be attributedspecifically to desorption-related effects. It is however impor-tant to note that our previous work revealed limited depen-dence between drug loading in a LBF and extent (percentage)of desorption from Neusilin R©15 suggesting that it is the prop-erties of the formulation that governs desorption performance,and this is elaborated in sections below. Nonetheless, at higherdrug loads, formulation performance is likely to reflect a bal-ance between desorption and precipitation and the subsequenteffects of digestion are also likely to impact on bioavailability.Under those circumstances, more complex in vitro testing pro-tocols might usefully be employed including in vitro digestiontesting.

In this study, preliminary experiments were undertaken todetermine whether the dispersion test conditions, namely, theintensity of mixing, the degree of dilution, and the nature of thedispersion media, had a significant effect on LBF desorptionfrom Neusilin R©. Dispersion studies were initially performedin SGF using IIIB-SEDDSNeusilin R© , a comparatively hydrophilicLBF (containing 60% hydrophilic surfactant) that disperses toform a microfine oil in water dispersion.22,29

Dispersion studies using a minipaddle apparatus revealedthat desorption of the IIIB-SEDDSNeusilin R© formulation fromthe carrier occurred slightly faster when the paddle speedwas higher. However, the extent of desorption was insensitiveto mixing intensity, and reached at best approximately 75%(Fig. 1). The fact that similar results were obtained in smallertest-tube experiments, where the samples were mixed only ev-ery 1 h, further confirms that the degree of mixing does notgreatly influence desorption of the LBF from Neusilin R©. Thisis consistent with our earlier study,15 where the use of veryhigh rates of shear (attained using a 25-mm diameter propellerrotating at ∼450 rpm in a volume of 40 mL) was not able tocompletely desorb the LBF from Neusilin R©, and recent workby Gumaste et al.16 that has reported incomplete desorptionof some LBFs from Neusilin R© despite the use of USP paddleapparatus at a 250 rpm agitation rate. The lack of an effectof shear intensity on desorption may reflect the effective en-trapment of the LBF within the mesopores because hydrody-namics within the pore network is likely to be independentof external shear. The results suggest that the extent of LBFdesorption from Neusilin R© will not be enhanced by mixing andshear forces within the gastrointestinal tract. It may be ar-gued that complete desorption may occur in vivo where theattainment of sink conditions as the drug and components ofthe LBF are absorbed in the intestine will promote formulationdesorption. Preliminary evidence in this submission, however,suggests that this may not be the case as transferring Neusilin R©

material, which contained residual LBF after initial dispersion,to fresh medium did not encourage further desorption (Fig. 4).This observation is also consistent with our previous workwhere incomplete LBF desorption observed in vitro translatedto poorer performance in vivo.15

In the current study, there was in fact evidence that des-orption of the LBF from Neusilin R© increased with decreasingdilution (Fig. 2). The mechanism for this effect is not clear, butpossible explanations include (1) a higher solubilizing capacityof the dispersed phase as a result of a lower volume of aque-ous media, in turn promoting further leaching of LBF and/orfrom the carrier or (2) the capacity for Neusilin R© to more effec-tively buffer the pH of the dispersion medium to a higher pHat higher concentrations.30 Measurement of solution pH in thepresence of differing dilution of Neusilin R© revealed measuredpH after a 1 in 250 dilution, a 1 in 80, and a 1 in 20 dilutionof 2.3, 3.3, and 3.5, respectively (see Supplementary Material).This is consistent with the apparent pKa of the silanol groups



that cover the Neusilin R© surface (3.5) and therefore the pH ofmaximum buffer capacity.30 It is plausible that the greater po-larity of the Neusilin R© surface at lower dilutions promoted thedesorption of the LBF; however, further work is necessary toverify this claim. It should also be noted that LBF desorption re-mained incomplete even under conditions of high-formulationmass relative to media volume (i.e., 0.5 g in 7 mL).

LBF Sensitivity to Desorption from Neusilin R©: Effect of Drug Type

The IIIB-SEDDSNeusilin R© formulation and a more lipophilic IIIA-SEDDSNeusilin R© formulation were used to probe the possibilitythat desorption from Neusilin R© was drug dependent. The des-orption characteristics of LBFs containing the neutral drugsdanazol and fenofibrate were largely consistent, with higherdesorption of the more hydrophilic IIIB-SEDDS formulationand, in the case of the more lipophilic IIIA-SEDDSNeusilin R© for-mulation, slightly higher desorption in SGF compared withSIF* (Fig. 5). Similarly, desorption of the LBFs containing theweak base cinnarizine was also highest in SGF, although thedifference in desorption performance across the different mediawas much more pronounced. In contrast, desorption of LBFscontaining mefenamic acid was less affected by media type,and in the case of the IIIA-SEDDSNeusilin R© formulation, showeda much greater desorption in SIF* compared with other drugs.

The interplay between drug type and medium type on des-orption characteristics is therefore complex, but is consistentwith the ionization behavior of the drug and the Neusilin R© sur-face. The surface of Neusilin R© in acidic conditions such as SGFwill be predominantly positively charged31–33 because of proto-nation of the surface silanol groups.32,33 As the majority of theweak base cinnarizine will also be positively charged in thiscondition (pKa 7.47), electrostatic repulsive effects between thecarrier and the drug in SGF may have contributed to greatercinnarizine desorption from Neusilin R© in SGF. Indeed, previ-ous work using simple drug/carrier mixtures (no LBF) has alsoreported increased desorption of a basic drug from a meso-porous silica material under acidic conditions.34 In contrast,under more neutral SIF* conditions, the surface of Neusilin R© isincreasingly negatively charged as silanol groups are deproto-nated. Similarly, mefenamic acid is predominantly negativelycharged in this medium (pKa 4.2). Therefore, in a manner anal-ogous to cinnarizine in SGF, electrostatic repulsion betweenthe surface of Neusilin R© and mefenamic acid may explain thehigher desorption of this drug in SIF* compared with otherdrugs. Similar effects of electrostatic repulsion leading to drugrelease have been reported previously for weakly acidic drugsadsorbed on mesoporous silica materials.35

In addition to electrostatic forces between drug and the sur-face of Neusilin R©, other mechanisms may also have contributedto drug and media differences in desorption. Neusilin R© under-goes a certain degree of dissolution under acidic conditions fol-lowing the release of silicic acid, and Mg2+ and Al3+ ions.30,36

Carrier dissolution is likely to contribute to LBF (and there-fore drug) desorption, and may therefore provide an alterna-tive explanation for the greater desorption of cinnarizine inSGF compared with SIF*. Carrier dissolution also provides anexplanation for the greater desorption in SGF of IIIA-SEDDScontaining neutral compounds. It is therefore likely that dis-solution of the carrier and electrostatic repulsion contributedto the large difference in cinnarizine desorption from the IIIA-SEDDSNeusilin R© formulation between SGF and SIF*. Carrier dis-

solution on the contrary is likely to have attenuated the differ-ence in mefenamic acid desorption between SGF and SIF*. It isalso possible that drug ionization and the subsequent increasein drug affinity for the aqueous phase relative to the LBF canin part explain the greater desorption in instances where thedrugs were increasingly ionized.

Overall, neutral compounds appeared to be most sensitiveto incomplete desorption of LBFs from Neusilin R© because thesecompounds did not benefit from any of the advantageous effectsof drug ionization on desorption. In the case of weak bases,greater desorption should be anticipated in the stomach, andin the case of weak acids, greater desorption in the intestine.

It was also apparent that the difference in desorption behav-ior of IIIA-SEDDS and IIIB-SEDDS remained significant (andconsistent) for each of the different drugs. This suggests thatLBF composition plays a more important role than drug typein determining formulation desorption from Neusilin R©.

LBF Sensitivity to Desorption from Neusilin R©: Effect of LBFComposition

Our previous study showed that a medium-chain SEDDS for-mulation more effectively desorbed from Neusilin R© when com-pared with a long-chain SEDDS, and that this difference wasevident both in vitro and in vivo.15 In another study, binarymedium-chain LBFs consisting of Capmul R© MCM–Cremophor R©

EL (7:3, w/w) or Captex R© 355–Cremophor R© EL (7:3, 1:1, and 3:7,w/w, ratios) did not completely (<80%) desorb from Neusilin R©

in 0.01 N HCl (∼pH 2), whereas ternary Captex R© 355, Capmul R©

MCM, and Cremophor R© EL formulations exhibited superiordesorption properties.16

In the first part of the present study, the IIIB-SEDDS formu-lation more effectively desorbed from Neusilin R© when comparedwith the more lipid-rich IIIA-SEDDS. This trend was evidentacross all four drugs in SGF and SIF*. Further studies usinga range of different formulations were carried out to explore ingreater detail the LBF sensitivity to this incomplete desorptionphenomenon (Fig. 8). Using 38 LBFs, it was clear that althoughincomplete desorption appeared to impact all tested formula-tions, the extent of desorption was formulation specific. The keydeterminants of desorption appeared to be surfactant concen-tration, surfactant HLB/chemistry and, to a lesser extent, lipidchain length.

Desorption of the LBF (and therefore the drug) decreasedwith increasing lipid–surfactant ratio. This is consistent withGumaste et al.16 who reported a trend toward decreasing des-orption of Captex R© 355–Cremophor R© EL lipid formulations asthe quantity of Captex (medium-chain triglyceride) increased.In the current study, the trend toward decreasing desorp-tion with increasing lipid–surfactant ratio was found to beconsistent for formulations comprising long-chain, medium-chain, and short-chain lipids, and five different surfactants.Although the impact of lipid–surfactant ratio on desorption re-mained significant across different formulations, the overalleffect was lower when formulations contained short-chain lipidand when they contained more hydrophilic surfactants (e.g.,Cremophors or Tween R© 80/20) instead of the more lipophilicTween R© 85. In terms of lipid chain length, there was evidencethat formulations containing short-chain triglyceride, namely,triacetin, exhibited greater desorption compared with medium-chain and long-chain equivalents. Triacetin, however, is an un-usual glyceride component of LBF and in the current study is



probably behaving more like a cosolvent than a traditionalglyceride lipid. Importantly, there were no obvious trends inthe behavior for the more common medium-chain and long-chain glyceride containing formulations. In practice, therefore,it seems likely that the chain length of glyceride lipid containingwithin an adsorbed LBF will have a limited effect on desorptionbehavior.

Collectively, the data suggest that the overall hydrophilicityof the formulation, and in particular the surfactant composi-tion, strongly affects LBF desorption. This is well exemplified inFigures 9b and 9c wherein desorption progressively increaseswith increased surfactant concentration and increased LFCSformulation class. This relationship suggests that the affinity ofthe formulation for the dispersion medium may play an impor-tant role in determining the extent of LBF desorption. Along-side this hypothesis is the possibility that other related factorscontributed to the much higher desorption of more hydrophilicLBFs (i.e., those rich in surfactant, poor in lipid). With increas-ing surfactant concentration, one would expect improved wet-ting of the Neusilin R© particles as the interfacial tension betweenthe formulation and the hydration medium is lowered. In ad-dition, there is the possibility that the surfactant may haveimproved the capillarity of the hydration medium, allowingbetter penetration into the Neusilin R© porous network, therebyimproving desorption. Although these additional factors do notchange the key findings of the present work, they do illustratethe complexity of the LBF desorption process, particularly froma porous construct such as Neusilin R©, and highlights the needfor further research in this field.

LBF Sensitivity to Desorption from Neusilin R©: Effect of LBFConcentration

The adsorption of a LBF onto the surface of an adsorbentand subsequent solidification of the formulation leads to de-crease in entropy. However, this loss of entropy is offset byfavorable surface–formulation interactions and an enthalpygain,37 thereby explaining the high LBF loading capacity ofNeusilin R© and other high-surface-area materials (e.g., Sylysia R©

and Fujicalin R©). The types of interaction between LBFs andNeusilin R© may include electrostatic attractions, hydrogen bond-ing, hydrophobic bonding, and, in the presence of residual waterin the formulation or on the surface of the silica, solvation anddesolvation. Larger molecules, such as lipids and surfactants,also offer the possibility of simultaneous interaction at multiplepoints on a surface.38 However, loading of a LBF onto Neusilin R©

to levels above monolayer surface coverage is expected to resultin additional layers of formulation that interact with surface-associated formulation and not the carrier. This “saturation” ofthe available surface is illustrated by the nitrogen physisorp-tion experiments in the current study (see Fig. 7), where theavailable surface area of Neusilin R© reaches zero (i.e., is satu-rated) on increasing the LBF–Neusilin R© ratio to 2:1. At this 2:1ratio, a proportion of formulation is therefore likely to be notdirectly bound to the carrier. This “labile” fraction of the formu-lation exhibits greater molecular mobility (as recently shownin a series of compelling NMR spectroscopy studies by Kutzaet al.39). The labile fraction of the formulation is expected todesorb first and to be more susceptible to desorption as thereare no strong LBF–Neusilin R© interactions to overcome. Evi-dence that increasing LBF–Neusilin R© ratio led to an increasein desorption (Fig. 6) supports this hypothesis. Further increas-

ing the LBF–Neusilin R© ratio, however, may not be beneficial asit is expected to lead to a decrease in flow properties and soon.13,20

Although not investigated here, it is likely that differentcarriers exhibiting a different specific surface area (i.e., inter-nal porosity), different pore structure, and different surfacechemistry may show different LBF desorption behavior. Forexample, Agarwal et al.13 compared LBF desorption from mag-nesium aluminium silicate, silicon dioxide, and calcium sili-cate adsorbents, and reported a lower extent of desorption withlower-adsorbent specific surface area. A lower specific surfacearea was said to increase the extent of formulation that wasin contact with the external surface of the adsorbent, whichwas in this case believed to promote drug (griseofulvin) crys-tallization on the adsorbent surface. Alongside the extent towhich formulation is bound to the Neusilin R© carrier, the affin-ity of the LBF toward the dispersion medium is an importantdeterminant of desorption potential. Indeed, previous studieshave reported differing rates of surfactant desorption from sil-ica and alumina surfaces with changing solvent polarity, consis-tent with changes to solvation energy as the surfactant entersbulk solution.37,40–42 Higher solvation energies are expected ontransfer of a more hydrophilic LBF from the adsorbed stateinto the dispersed phase, and this is likely to explain, at leastin part, the increase in LBF desorption with decreasing lipid–surfactant ratio in the formulation (Figs. 8 and 9b, and pre-viously Ref.16). Furthermore, for the less hydrophilic formu-lations, the lower solvation energy dictates that the extent ofLBF desorption is more highly dependent on the strength ofsurface–formulation interactions. This effect is evident in thepresent study where, in Figure 6, the hydrophilic IIIB-SEDDSformulation at a low LBF–Neusilin R© ratio (and therefore wherea higher proportion of the LBF was expected to directly interactwith the Neusilin R© surface and therefore to be “tightly bound”)was still more readily desorbed than the lipid-rich IIIA-SEDDS,even when the latter was formulated at a high LBF–Neusilin R©

ratio (and therefore where a higher fraction of the LBF wasexpected not to interact directly with the Neusilin R© surface andtherefore, to be more loosely bound). Thus, it appears that theimportance of solvation is such that formulations tightly boundto the surface of Neusilin R© may still readily desorb if the affinityfor the dispersion medium is sufficiently high, indicating thatdesorption extent is dictated most by formulation composition.

It has been shown previously that LBFs are not typically ho-mogenously distributed over Neusilin R© particles.39 It is there-fore possible that the labile formulation fraction progressivelymigrates on storage to formulation-free regions on the adsor-bent, and possibly deeper within the pore network of Neusilin R©.This would result in a higher proportion of the formulation di-rectly interacting with the Neusilin R© surface, and because thisfraction of the LBF is expected to be more difficult to desorb, itprovides a plausible explanation for the diminished LBF des-orption from Neusilin R© following a period of 1-month storage(Fig. 10). Further support for this hypothesis may be drawnfrom the fact that the more lipophilic formulations were mostsusceptible to storage effects because the lower solvation en-ergy of these formulations dictates that Neusilin R© surface–LBFinteractions are more significant drivers of the extent of des-orption. Formulation viscosity may also play a role becausethe formulations most prone to storage effects were also theleast viscous LBFs, that is, those high in lipid and particularlythe medium-chain lipid. Additional studies are necessary to



determine whether the more mobile fractions of an adsorbedlipid formulation relax on storage and more extensively inter-act with the surface of the adsorbent or whether the viscosity ofthe formulation determines to what extent a LBF may migrateonce adsorbed onto Neusilin R© material.

It has been recently proposed that formulation gelling ten-dency and the ability for these gels to block the Neusilin R© porescan explain incomplete LBF desorption.16 Under these circum-stances, desorption may be low, even in instances when theformulation is relatively hydrophilic. For example, Gumasteet al.16 suggested that formulations consisting of Cremophor R©

EL and medium-chain triglyceride formed gels that limitedLBF desorption from the carrier Neusilin R©. Previous work us-ing nonsolidified LBFs has also reported gel formation forCremophor R© EL formulations containing medium-chain triglyc-eride and monoglyceride in 2:143 (also the ratio utilized in thiswork) and 1:2 lipid blends.44 Both of these studies report ahigher propensity for gelling when surfactant content exceeds35% of the formulation. Interestingly, however, the results de-scribed here are not consistent with a scenario where gel forma-tion limits LBF desorption from Neusilin R© as we see the oppo-site effect, namely, higher desorption on increasing surfactantcontent (and therefore increased risk of gel formation). In ad-dition, desorption of formulations containing Cremophor R© sur-factants was similarly efficient, if not greater than the equiv-alent Tween R© formulations, even though the latter typicallyexhibit much lower gel-forming tendency. Therefore, althoughit is conceivable that gel formation may limit the extent of LBFdesorption, this appears unlikely to fully explain the resultsreported here. Instead, the overall drivers behind incompleteLBF desorption from Neusilin R© appear to be a combination ofthermodynamic factors, such as the strength of the interactionsbetween the LBF components and the carrier surface, and ki-netic/steric factors such as water penetration or gel formationin the pores.

LBF Desorption Approaches Balanced Against ConventionalLiquid Filling

The main driver for research in this field is the potential to con-vert liquid/semi-solid lipid formulations into free-flowing pow-ders so that they may be filled into capsules or compressedinto tablets. As described in the Introduction, a powder in cap-sule LBF product may be formed from a lipid absorbed carrierwithout the need for significant additional formulation, andit may also be possible to convert a significant mass of LBFdesorbed powder into a tablet (although the formulation ef-forts to achieve this goal are typically more significant). Thesesolid dose approaches to LBF may be particularly attractivefor companies that lack in-house facilities for capsule liquid-filling. However, there are also downstream challenges to thesuccessful development of solidified LBFs. These include first,process-related issues, namely the increased formulation bulkassociated with an adsorbent (and any additional excipientssuch as binders and/or disintegrants) that can limit the drugloading per capsule or tablet, and the work required to en-sure adequate flow properties such that liquid-loaded powderscan be rapidly converted to robust final dosage forms. Second,there are the biopharmaceutical challenges such as those high-lighted here and in our previous work,15 where there is therisk that LBF performance will deteriorate following adsorp-tion onto a carrier such as Neusilin R©. These challenges must

therefore be considered alongside the potential advantages ofsolidifying lipid-based formulations, and the realization that re-cent advances in equipment and process development relatedto liquid-filling of hard capsules has also improved the applica-bility of traditional liquid-filling techniques.45

CONCLUSIONS

Previous evidence suggests that adsorbing lipid formulationsto high-surface adsorbents such as Neusilin R© US2 (mesoporousmagnesium aluminometasilicate) may result in decreased per-formance when compared with equivalent liquid formulations.The current study reinforces this suggestion and shows thatthis occurs across a broad range of drugs, formulations andin vitro testing conditions. In addition, the data provide evi-dence that storage of adsorbed formulations can further dimin-ish performance, possibly as mobile fractions of the formulationmigrate deeper within the porous architecture. Increasing thehydrophilicity and quantity of surfactant in the formulationprovides a means to enhance desorption from Neusilin R©, al-though desorption was incomplete in all cases. Thus, althoughsolidification approaches offer the beneficial opportunity to con-vert lipid formulations into free-flowing powders, this must bebalanced against the risk that the formulation will not com-pletely desorb from the adsorbent and that this will reduce inin vivo performance. Subsequent studies will usefully seek toidentify the most appropriate combinations of lipid formula-tion and carrier such that adsorption is sufficient to promotesolidification, but that desorption is not hindered.

ACKNOWLEDGMENTS

M.V.S. acknowledges the Institute for the Promotion of In-novation through Science and Technology in Flanders (IWT-Vlaanderen) for a PhD grant and the Research Foundation-Flanders (FWO) for a travel grant for a long stay abroad.

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