Effect of formulation additives on drug transport through size-exclusion

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Effect of formulation additives on drug transport through size-exclusion membranes Enik# Borbás, Petra T#zsér, Konstantin Tsinman, Oksana Tsinman, Krisztina Takacs-Novak, Gergely Völgyi, Balint Sinko, and Zsombor Kristof Nagy Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00343 • Publication Date (Web): 29 Jun 2018 Downloaded from http://pubs.acs.org on June 30, 2018

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Molecular Pharmaceutics

Effect of formulation additives on drug transport through size-exclusion membranes Enikő Borbás1, Petra Tőzsér1, Konstantin Tsinman2, Oksana Tsinman2, Krisztina TakácsNovák3, Gergely Völgyi3, Bálint Sinkó2, Zsombor K. Nagy1* 1

Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest 1111, Hungary 2

3

Pion Inc., Billerica, Massachusetts 01821, United States

Department of Pharmaceutical Chemistry, Semmelweis University, Budapest 1092, Hungary

*Budapest 1111, Hungary, 3 Muegyetem rakpart, [email protected]

Abstract The aim of this research was to investigate the driving force of membrane transport through sizeexclusion membranes and to provide a concentration-based mathematical description of it to evaluate whether it can be an alternative for lipophilic membranes in formulation development of amorphous solid dispersions. Carvedilol, an anti-hypertensive drug, was chosen and formulated using solvent-based electrospinning to overcome the poor water solubility of the drug. Vinylpyrrolidone-vinyl acetate copolymer (PVPVA64) and Soluplus® were used to create two different amorphous solid dispersions of the API. The loaddependent effect of the additives on dissolution and permeation through regenerated cellulose membrane

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was observed by a side-by-side diffusion cell, µFLUXTM. The solubilizing effect of the polymers was studied by carrying out thermodynamic solubility assays. The supersaturation ratio (SSR, defined as the ratio of dissolved amount of the drug to its thermodynamic solubility measured in exactly the same medium) was found to be the driving force of membrane transport in the case of size-exclusion membranes. Although the transport through lipophilic and size-exclusion membranes are mechanistically different, in both cases the driving force of membrane transport in the presence of polymer additives was found to be the same. This finding may enable the use of size-exclusion membranes as an alternative to lipid membranes in formulation development of amorphous solid dispersions. KEYWORDS dissolution-permeation, size-exclusion membrane, transport, carvedilol, supersaturation ratio, driving force, flux, microflux ABBREVIATIONS CAR, Carvedilol; ASD, amorphous solid dispersion; API, active pharmaceutical ingredient; BCS, biopharmaceutical classification system; SSR, supersaturation ratio; DSC, differential scanning calorimetry; SEM, scanning electron microscopy; XRD, X-ray powder diffraction

1. INTRODUCTION The dissolution enhancement of BCS II classified (poorly water-soluble, but highly permeable) active pharmaceutical ingredients (APIs) have recently become the focus of attention on the field of formulation development.1,2 Although in vitro dissolution tests are most commonly used to characterize drug formulation in the development phase, the results of this test do not always correlate with in vivo bioavailability.3 The lack


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of correlation is in many cases due to the fact that by using solubilizing agents as formulation additives, not only the solubility and dissolution of the drug, but also the partition coefficient changes between the aqueous and lipophilic phase and in this way the speed of membrane transport (permeability) is altered. This phenomenon is the so-called solubility-permeability interplay, described in detail by Dahan & Miller4 and reported by various authors5–8. In many cases, it was demonstrated in vitro and in vivo as well that the use of cyclodextrins to increase the solubility of an API leads to the decrease in the apparent permeability.9–11 Moreover, the decrease in the apparent permeability was found to be proportional to the solubility enhancement achieved by the complexing agent.12,13 Although a similar interplay between solubility and permeability of an API was already discovered a long time ago in vitro in the case of surfactants14–17, the first in vivo data on the effect of surfactants was only published in 201518. Not only does the complexation or micellar solubilization of the API lead to decreased permeability, but so does the use of hydrotropic agents like co-solvents, or PEG-40019–21. While solubilizing additives yield an improvement in the aqueous solubility, this comes with a decrease in permeability; it seems that the amorphous form of the API has the ability to overcome this trade-off. The amorphous state of the API leads to an increased apparent solubility, higher than the equilibrium crystalline solubility,22,23 meaning supersaturated solutions are created when dissolving amorphous drugs. Increased fluxes, compared to results from saturated or subsaturated solutions, were reported in many cases when supersaturated solutions were used5,24–26. These results confirm that amorphous solid dispersions (ASDs) have a great potential to improve the bioavailability of poorly water-soluble drugs. Electrospinning (ES) is a flexibly scalable and continuous technology to generate ASDs27–34.No matter how many working fluids are treated simultaneously, the generated fibers-based ASDs are always collected in the physical forms of non-woven membranes.35,36 Polymer additives, like PVP derivatives8 commonly used for electrospinning or any other formulation method producing ASDs, generally do not



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alter the equilibrium crystalline solubility of APIs.37 Instead polymers are responsible for making the API’s supersaturation last longer in solution by inhibiting precipitation and crystal growth.38 In some special cases polymers can even modify the solubility, like the non-ionic surfactant Soluplus8,39. The flux results of ASDs and solubilizing-additive-containing formulations clearly show in vivo and in vitro (Caco-2 and lipid membranes) that the driving force of membrane transport cannot be simplified to the concentration gradient, especially in cases where solubility is altered. The driving force of membrane transport in the case of lipophilic membranes was found to be the SSR (defined as the ratio of dissolved amount of the drug to its thermodynamic solubility measured in exactly the same medium with the same excipient concentration).8 Surprisingly, in the case of studying flux across regenerated cellulose-based size-exclusion membranes, similar patterns in solubility and permeability were observed when using solubilizing agents on the donor side.40,41 This is an interesting phenomenon because the transport of pure API is mechanistically different through lipophilic and size-exclusion membranes. In the case of transport through a lipid membrane, there are two aqueous phases separated by an apolar organic phase; this way the drug molecule first has to partition from the first aqueous phase into the organic phase to start diffusing there and then has to partition again into the acceptor phase.42 In the case of size-exclusion membranes, there is no partitioning process because the membrane, the donor and the acceptor side are filled with the same buffer solution; therefore, it measures a transport speed through an aqueous media, and not a organic phase like lipophilic membranes. The other important difference between the two types of membrane is how they distinguish the drug molecules. Only neutral species are able to efficiently cross the lipophilic membranes according to the pH-partition hypotheses43, while all ionized and neutral species are able to cross cellulose membranes, unless their transport is limited by their hydrodynamic size.


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Not just the mechanism but the application of the two membrane types differ as well. The celluloseacetate-based size-exclusion membranes are widely used in pharmaceutical research for characterization of the drug-release kinetics from microdisperse systems44 and for particle size measurement of aggregates, micelles or cyclodextrin complexes using different molecular weight cut-off membranes45. Recently, cellulose membranes were also applied in the description of the liquid-liquid phase separation phenomenon in highly supersaturated solutions of lipophilic drugs.24 Moreover, these membranes are used to model absorption of digested food in the intestines since they exclude macromolecules (like starch) and only let small digestive products (like maltose) permeate. A diffusion cell with lipid membrane aims to be predictive of passive permeation of the drug molecules through biological membranes. Therefore, use of biorelevant conditions, like the pH gradient, and tissue-specific lipid compositions30,46–48, have shown a good correlation with in vivo human intestinal absorption data47,49,50 in the case of pure APIs. Although size-exclusion membranes are permeable to ionized molecules and therefore cannot provide a good approximation of in vivo passive transcellular permeation properties in the case of pure APIs, unlike lipid membranes do, they might be a simple and sufficient tool to differentiate formulations containing different excipients but the same API. For that reason, the aim of this paper is to investigate the driving force of membrane transport for size-exclusion membranes and provide a concentrationbased mathematical description of it to evaluate whether it can be an alternative for lipophilic membranes in the case of studying drug formulations of the same API. Carvedilol (CAR) an anti-hypertensive drug was chosen as a poorly water-soluble model drug. It was processed to create an ASD by using solvent-based electrospinning and vinylpyrrolidone-vinyl acetate copolymer (PVPVA64) or Soluplus® as polymer additives. The load-dependent effect of the polymers was studied by simultaneous dissolution-permeation experiments and thermodynamic solubility assays.



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2. EXPERIMENTAL SECTION 2.1. Materials Carvedilol (406.482 g/mol, structure shown in Figure 1), buffer components (NaH2PO4, NaOH, KCl, NaCl, HCl solution) were purchased from Sigma-Aldrich Co. LLC. (St. Louis, MO, USA). Soluplus® (structure shown in Figure 1, average molecular weight 90 000–140 000 g/mol) and PVP VA64 (average molecular weight 24 000–30 000 g/mol were obtained from BASF (Ludwigshafen, Germany).

Figure 1. Structure of Carvedilol and the polymer additives

2.2. Electrospinning The polymer and CAR calculated amounts were added into 8 mL of the solvent (ethanol) and stirred magnetically (VELP Scientifica, Usmate, Italy) at 600 rpm until the dissolution was complete. The electrical potential applied on the spinneret electrode (inner diameter 0.8 mm) was 25 kV (NT-65 high voltage DC supply, MA2000 device, Unitronik Ltd, Nagykanizsa, Hungary). A grounded aluminum plate covered with aluminum foil was used as collector (20 cm from the spinneret). Polymer solutions were dosed with 4–8 mL/h at room temperature (25 °C) with an SEP-10S Plus type syringe pump (Aitecs, Vilnius, Lithuania). The composition of polymer solutions is shown in Table 1.


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Table 1. Composition of the polymer solutions Ethanol Formulation

named

Polymer

after

(mL/g dry

API (w/w %) containing polymer

(w/w %) matter )

ES_PVP VA64

12

88

3.5

ES_Soluplus

12

88

3.5

2.3. Scanning Electron Microscopy The morphology of the samples was investigated with a JEOL JSM-6380LA (JEOL Ltd., Tokyo, Japan) type scanning electron microscope. Each specimen was fixed by conductive double-sided carbon adhesive tape and coated with gold-palladium alloy before examination. The applied accelerating voltage and working distance were 15 kV and 16 mm, respectively.

2.4. Differential Scanning Calorimetry Differential scanning calorimetry (DSC) measurements were carried out using a Setaram DSC 92 apparatus (Caluire, France). (Sample weight: 10–15 mg, open aluminum pan, nitrogen flush.) The temperature program consisted of an isothermal period (1 min) at room temperature, with subsequent linear heating from 25 °C to 150 °C at the rate of 10 °C/min.

2.5. X-ray powder diffraction X-ray diffraction patterns of the samples were recorded by means of a PANalytical (Amelo, the Netherlands) X’pert ProMDP X-ray diffractometer using Cu-K" α radiation (1.542 Å) and a Ni filter.



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The applied voltage was 40 kV, while the current was 30 mA. The samples were analyzed between 5° and 42° 2θ.

2.6. Measurement of the thermodynamic solubility with saturation shake flask method For measuring the thermodynamic solubility crystalline CAR Form I (5 mg) were added to 10 mL of 33 mM pH 6.5 phosphate buffer already containing the calculated amount of formulation additive (n = 3). The resulting mixtures were stirred at 25 °C for 6 h (to the solution equilibrium) followed by 18 h of sedimentation as recommended in the optimized protocol of shake flask method.51,52 Without filtration the concentration of the API in the saturated solution was determined by the immersed UV-probes of the µDiss (Pion Inc., Billerica MA, USA) apparatus based on a former calibration. For the evaluation of the concentrations, 5 mm tips and second derivative spectra were used. 2.7. In vitro dissolution-permeation study In vitro dissolution-permeation studies were carried out using a µFLUX (Pion Inc., Billerica MA, USA) apparatus (Figure 2). It consists of a donor and an acceptor chamber (20 mL volumes) separated by an artificial membrane selected to be a size-exclusion membrane for this study (Ultracel® regenerated cellulose, MWCO 1 kDa, 1.54 cm2, Merck KGaA, Darmstadt, Germany). At first, the membranes were soaked in the pH 6.5 phosphate (33 mM) buffer overnight, then 18 mL of pH 6.5 phosphate buffer was added into the donor and acceptor chambers. The pure drug powder or the formulations were placed into the donor chamber (n = 2–3). Both chambers were stirred at 150 rpm at 25 °C. In both chambers the API concentration was measured in real time by immersed UV-probes connected to the Rainbow instrument (Pion Inc., Billerica MA, USA). 5 mm pathlength tips on the donor and 20 mm pathlength tips on the acceptor probes were used. For the evaluation of the concentrations, second derivative spectra were used. The flux across the membrane was calculated using the following equation:


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J(t)=

where the flux (J) of a drug through the membrane is defined as the amount (n) of drug crossing a unit area (A) perpendicular to its flow per unit time (t).

Figure 2. Schematic figure of the µFLUXTM apparatus.

3. RESULTS AND DISCUSSION 3.1. Characterization of CAR containing formulations 3.1.1. Morphology ES_PVP VA64

ES_Soluplus

Figure 3. Scanning electron microscopic images of carvedilol containing electrospun formulations (PVP VA64 based on the left, Soluplus based on the right)



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Scanning electron microscopic (SEM) images show that with PVP VA64 beaded nano- and microscaled fibers were formed, while with Soluplus beadless nanoscaled electrospun fibers were obtained (Figure 3). Changing the polymer concentration can vary the solution viscosity and higher viscosity favors formation of fibers without beads.53 The sufficient polymer concentration to enable fiber formation differs for different polymers. The two polymers were used in the same concentration in the electrospinning solution (2g polymer/8 mL ethanol): with Soluplus this polymer concentration was high enough to achieve sufficient entanglements of the linear polymer in solution, this way enabling beadlesfiber formation54, while for PVP VA 64 the same polymer concentration was not enough in solution, this way only beaded fibers were produced. 3.1.2. X-ray powder diffraction

Figure 4. X-ray diffractograms of pure CAR (form II) and its formulations (a) CAR (form II), (b) physical mixture of CAR_PVP VA64 (12:88), (c) ES_PVP VA64, (d) physical mixture of CAR_Soluplus (12:88), (e) ES_Soluplus X-ray powder diffraction (XRD) was used to characterize the morphological changes of CAR induced by electrospinning. Figure 4 shows the diffractograms of the ES samples compared to the crystalline API and the physical mixtures. In the case of the physical mixtures (b,d), the characteristic peaks of the


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crystalline drug were clearly observed. While in the case of the formulation (c,e), no diffraction peaks were seen but only a diffuse background scattering as a proof of the amorphous nature of all the samples. 3.1.3. Differential Scanning Calorimetry

Figure 5. DSC thermograms of pure CAR (form II) and its formulations (a) CAR (form II), (b) physical mixture of CAR_PVP VA64 (12:88), (c) ES_PVP VA64, (d) physical mixture of CAR_Soluplus (12:88), (e) ES_Soluplus Differential scanning calorimetry analyses were also performed in order to study the physical state of the components in the samples. DSC thermograms (Figure 5) showed that CAR had a melting endotherm with a maximum at 114 °C; this melting peak could also be observed in the physical mixture. The absence of a melting peak in the CAR-containing electrospun formulations lead to the conclusion that the drug is in an amorphous form according to DSC results. Based on the SEM, XRD and DSC results dissolution enhancement was expected because of the high surface area and the amorphous state of the API.



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3.2 Thermodynamic solubility

Figure 6. CAR (form I) solubility in pH 6.5 phosphate buffer as a function of polymer additive concentration For the thermodynamic solubility studies, CAR form I was used because this polymorphic form was found to be more stable55 than form II, which was used in commercially available formulations. Compared to literature data on the solubility of form II at pH 6.556, the measured solubility of form I is around half of the solubility of the other polymorph. From the thermodynamic solubility results shown in Figure 6 it can be concluded that the addition of PVP VA64 to the dissolution media in the concentration range 0–600 µg/mL did not cause a significant enhancement in the thermodynamic solubility of the API. Applying the PVP VA64 in higher concentrations resulted in a gradual increase in the solubility of CAR. The addition of Soluplus showed a similar tendency of the solubility curve, except the solubilization of the API started at lower additive concentration. At 1500 µg/mL additive concentration, the solubility reached with Soluplus was found to be almost twice as high as the solubility in the presence of PVP VA64. 3.3. In vitro dissolution-permeability study on µFLUX™ platform


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Figure 7. CAR concentration in the donor (left) and the acceptor (right) compartments ( (a) 16 µg/mL (b) 55 µg/mL (c) 130 µg/mL API load, pH 6.5 buffer in the donor and acceptor compartment, sizeexclusion membrane (1kDa MWCO), 150 rpm, 25 °C For the two formulations and the pure API, 8–12 different loads were applied with the theoretical maximum CAR concentration varying from 16 to 250 µg/mL in the donor chamber (for detailed flux data see Supporting information). From these the results of 3 different loads (16 µg/mL, 55 µg/mL and 100 µg/mL of CAR) are presented in Figure 7. They were chosen for the interpretation of the thermodynamic solubility results (Figure 6). Figure 7.a shows the results for 16 µg/mL CAR load, which also defines the polymer concentration to be 117 µg/mL. At this polymer concentration no significant solubility enhancement was observed in the case of either additive (Figure 6). With approximately the same solubilities and donor concentrations (Figure 7.a) the concentration-time profile in the acceptor chamber also shows very similar flux results for the pure API and both formulations (Table 2). Figure 7.b shows the dissolution-permeation results for 55 µg/mL CAR loads (403 µg/mL polymer load). In this concentration region of the polymers, Soluplus already solubilizes the API (Figure 6), while in the case PVP VA 64 solubilization is not yet significant. Such API concentration is well above its solubility


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at pH 6.5, so this concentration was achieved by pre-dissolving CAR in pH 1.6 solution (Carvedilol is a weak base with pKa 7.8, its solubility is pH dependent, and in acidic media is higher than in neutral or higher pHs56) and changing the pH of the solution to pH 6.5 with concentrated phosphate solution containing sodium hydroxide57. It can be seen from the acceptor results and from the calculated fluxes (Supporting information) that while the flux from the pure API and from the PVP VA64 containing ASD was found to be very similar, the flux from the Soluplus based ASD was found to be almost halved. Figure 7.c shows the results for 130 µg/mL load, meaning 953 µg/mL polymer concentration. At this polymer concentration, both PVP VA64 and Soluplus were found to act as solubilizers (Figure 6). Soluplus enhanced the solubility of the API to a greater extent and resulted in a more prominent decrease in flux than PVP VA64. In conclusion, the dissolution-permeation and solubility results show quite clearly that enhanced solubility (regardless of the mechanism of solubilization: micelles or secondary bonds) leads to decrease in flux results.



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4. MATHEMATICAL DESCRIPTION OF MEMBRANE TRANSPORT FOR SIZEEXCLUSION MEMBRANES 4.1 Description for the transport of the pure API

Figure 8. Transport model diagram, depicting two aqueous chambers separated by a size-exclusion membrane. The drug molecules are introduced in the donor as pure API. The transport of the pure API through porous membrane is most commonly described by Fick’s first law of diffusion (Eq.1), very similar to bulk diffusion, except that the diffusivity is called effective diffusivity to account for the longer diffusive pathway in porous media. =

(Eq.1)

where J is the flux, c0m and chm are the concentrations of the solute within the membrane at the two water-membrane boundaries (Figure 8) and where Dm is the effective diffusivity of the solute within the membrane. Considering that the concentration at the donor side of the membrane ( the bulk of the donor media (

) equals the concentration in

) (Eq.2) and the concentration at the acceptor side of the membrane (

)

equals the concentration in the bulk of the acceptor media ( ) (Eq.3) and substituting these into Eq.1,


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flux can be expressed as Eq.4. Separating the constant and variable parameters in Eq.4, Eq.5 was created, where the constants were merged into one parameter called the effective permeability (Pe). (Eq.2) (Eq.3) J=Dm

=Dm

J=

(Eq.4) =Pe

(Eq.5)2

From Eq.5, it can be seen that in the simple case when only the pure API is present, the driving force of membrane transport through the porous membrane is the concentration gradient. At the very beginning of the dissolution-permeation experiments, there was no API in the acceptor chamber. This was the reason why an assumption could be made that the concentration of the API was zero in the acceptor chamber, meaning the flux only depends on the concentration in the donor compartment: J=Pe

(Eq.6.)

Based on Eq.6, the flux results of pure API and CAR containing ASDs are shown in Figure 9 as a function of concentration reached in the donor chamber. The slope of lines are equal to the effective permeability.



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Figure 9. Flux of pure CAR and CAR containing ASDs at 25 °C as a function of concentration in the donor chamber It can be seen from Figure 9 that in the case of the pure API, the donor concentration was directly proportional to the flux up to 140 µg/mL. In the case of Soluplus containing ASD, direct proportionality between flux and the CAR concentration was only true for low Soluplus concentrations. The slope of the curve rapidly changed around 30 µg/mL CAR concentration, which equals 215 µg/mL in polymer concentration. This rapid decrease in the slope suggests that though the CAR concentration in solution increases the amount of API that is able to cross the membrane, it is not increasing with the same rate. This phenomenon was most probably caused by Soluplus micelles, solubilizing the API, but forming bigger aggregates than the molecular weight cut-off of the membrane (1 kDa). The polymer concentration at which the slope decrease occurred was in good agreement with the solubility results (Figure 6) where Soluplus showed to significantly enhance the solubility of the API in higher than 300 µg/mL additive concentrations. Although the increased solubility due to the addition of the non-ionic surfactant might seem a trivial phenomenon, in the case of Soluplus the effect on solubility seems rather API-specific since decrease in solubility of the API has been also reported8.


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PVP VA64 shows a similar effect on the flux-concentration curve only at higher CAR concentration (80 µg/mL) and accordingly higher polymer concentration (595 µg/mL). This polymer concentration was found to be in agreement with the solubility results, where higher than 600 µg/mL additive concentration could significantly enhance the solubility of the API. This phenomenon is surprising in the case of the PVP VA64 because its ability to form micelle-like structures in aqueous solution in the presence of API has not yet been reported in the literature to the author’s knowledge. Although the interaction between CAR and PVP VA64 in aqueous solution has not been yet investigated, the orienting effect of PVP through secondary bonds with CAR during controlled crystallization is a known phenomenon.58 In conclusion, Eq.6 was valid for the pure API, but only valid for a limited concentration range in the presence of polymer additives. The effective permeability of the API was found to be changing at higher additive concentration, as a result of solubilization of the API (due to micellization or secondary bond) in the donor chamber. These results indicate that Eq. 6 was only valid for the pure API, but could not describe the driving force in the presence of solubilizing additives. 4.2 Description for the transport of the API from ASDs containing polymers with high molecular weight



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Figure 10. Transport model diagram, depicting two aqueous chambers separated by a membrane barrier. The drug molecules are introduced in the donor chamber in formulation containing polymers instantly dissolving in the donor chamber, but not passing through the membrane. To find the universal driving force of membrane transport for size-exclusion membranes, independent from the type of formulation or additive, mathematical description is needed, which takes into account the solubility-permeability trade-off as well. The driving force can be derived from Fick’s first law (Eq.1). It is important to note that although in the case of size-exclusion membranes the donor and acceptor chamber and also the membrane pores are originally filled with the same media, when polymer additives are dissolved in the donor chamber and cannot cross the membrane because of their size, a modified donor media is created. In this media, the thermodynamic solubility of the API can differ from the solubility in the original buffer. The size-exclusion membrane separating these two solutions creates a phase boundary on the donor side of the membrane (Figure 10). In this case, the partitioning of the API between the solvents has to be considered (Eq.7). =

(Eq.7)

where Kd is the partition coefficient between donor compartment and membrane for steady state, cD is the concentration in the donor chamber, cm is the concentration in the membrane, * is the property at saturation. From Eq.7

can be expressed as:

(Eq.8) Considering that the concentration at the acceptor side of the membrane ( the bulk of the acceptor media ( ):


) equals the concentration in

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(Eq.9) If Eq.8 and Eq.9 is substituted to Eq.1: =

) (Eq.10)

Since the pores of the membrane are filled with the same media as the acceptor chamber, substituted with

can be

, resulting Eq.11. )=

) (Eq.11)

From Eq.11, it can be concluded that the driving force of membrane transport is the difference between the relative concentrations in the donor and acceptor compartment. This difference is directly proportional to the flux, and the coefficient of proportionality is

. This coefficient of

proportionality is a constant for a specific API when a specific membrane is used. This constant (B) can be defined for each API separately, like permeability, except B’s (Eq.10) value does not depend on the solubility of the API in donor and acceptor compartments. =

(Eq.12)

Considering that solubility in the donor could be influenced by formulation additives, Eq.13 could be used for expressing flux when measuring formulations and not just the pure API. J=B (

(Eq.13)

Usually in the beginning of the experiment, the relative concentration in the acceptor is negligible compared to

. For that reason, the flux results of CAR containing ASDs are shown in Figure 11 as a

function of only cD/cD*.



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Figure 11. Flux as a function of supersaturation ratio defined as the ratio of the donor concentration and the thermodynamic solubility of the API in the same media Figure 11 shows that the flux was directly proportional to SSR in the case of both formulations and the pure API. Comparing the slopes of lines shown in Figure 11 with homogeneity of slopes test, it can be concluded that the slopes of lines in the case of Soluplus, PVP VA64 containing formulations and the pure API did not differ significantly (p=0.5303). This means that the coefficient of proportionality is truly constant for Soluplus and PVP VA64 containing formulations.


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5. CONCLUSION While polymer additives generally did not act as solubilizing agents, Soluplus and PVP VA64 were found to increase the thermodynamic solubility of poorly water-soluble Carvedilol: the presence of 1467 µg/mL polymer resulted in 68.3 µg/mL solubility in the case of PVP VA 64 and 131 µg/mL solubility in the case of Soluplus, whereas the CAR concentration of saturated solution without additives was only found to be 37.7 µg/mL at pH 6.5. Although Soluplus was found to be almost twice as powerful as PVP VA64 in solubilizing CAR, the amount of drug permeated through the size-exclusion membrane was found to be significantly smaller in the case of Soluplus-containing formulations. These findings highlighted that simultaneous dissolution-permeation studies could be a useful tool for the selection and optimization of polymer matrixes for ASD-based formulations. Supersaturation ratio (SSR, defined as the ratio of dissolved amount of the drug to its thermodynamic solubility measured in exactly the same media) was found to be the driving force of membrane transport as a result of concentration-based mathematical description in the case of size-exclusion membranes. It was shown that although the transport through lipophilic and size-exclusion membranes seemed to be mechanistically different, in both cases the driving force of membrane transport in presence of additives was found to be the same. This finding may enable the use of size-exclusion membranes as an alternative to lipid membranes in formulation development (in the case that the additive cannot cross the membrane). SUPPORTING INFORMATION Flux results and donor concentration measured during in vitro dissolution-permeability study on µFLUX™ platform



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ACKNOWLEDGEMENT We thank our colleagues Dr. Zoltán Hórvölgyi and Dr. János Bódiss from the Department of Physical Chemistry and Material Science (Budapest University of Technology and Economics) who provided insight and expertise that greatly assisted the research. This project was supported by the New Széchenyi Plan (project ID: TÁMOP-4.2.1/B-09/1/KMR-2010-0002), Supported by the ÚNKP-17-3-I and the ÚNKP-17-4-II New National Excellence Program of the Ministry of Human Capacities, OTKA grants KH-124541 and PD-121051, FIEK_16-1-2016-0007, BME-KKP and the János Bolyai Research Scholarship of the Hungarian Academy of Sciences.


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Figure 1. Structure of Carvedilol and the polymer additives 70x78mm (300 x 300 DPI)



Figure 2. Schematic figure of the µFLUXTM apparatus 60x45mm (600 x 600 DPI)


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Figure 3. Scanning electron microscopic images of carvedilol containing electrospun formulations (PVP VA64 based on the left, Soluplus based on the right) 59x22mm (600 x 600 DPI)



Figure 4. X-ray diffractograms of pure CAR (form II) and its formulations (a) CAR (form II), (b) physical mixture of CAR_PVP VA64 (12:88), (c) ES_PVP VA64, (d) physical mixture of CAR_Soluplus (12:88), (e) ES_Soluplus 70x62mm (600 x 600 DPI)


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Figure 5. DSC thermograms of pure CAR (form II) and its formulations (a) CAR (form II), (b) physical mixture of CAR_PVP VA64 (12:88), (c) ES_PVP VA64, (d) physical mixture of CAR_Soluplus (12:88), (e) ES_Soluplus 67x56mm (600 x 600 DPI)



Figure 6. CAR (form I) solubility in pH 6.5 phosphate buffer as a function of polymer additive concentration 77x75mm (600 x 600 DPI)


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Figure 7. CAR concentration in the donor (left) and the acceptor (right) compartments ( (a) 16 µg/mL (b) 55 µg/mL (c) 130 µg/mL API load, pH 6.5 buffer in the donor and acceptor compartment, size-exclusion membrane (1kDa MWCO), 150 rpm, 25 °C 79x39mm (600 x 600 DPI)





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Figure 8. Transport model diagram, depicting two aqueous chambers separated by a size-exclusion membrane. The drug molecules are introduced in the donor as pure API. 254x190mm (300 x 300 DPI)


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Figure 9. Flux of pure CAR and CAR containing ASDs at 25 °C as a function of concentration in the donor chamber 74x70mm (600 x 600 DPI)



Figure 10. Transport model diagram, depicting two aqueous chambers separated by a membrane barrier. The drug molecules are introduced in the donor chamber in formulation containing polymers instantly dissolving in the donor chamber, but not passing through the membrane. 254x190mm (300 x 300 DPI)


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Figure 11. Flux as a function of supersaturation ratio defined as the ratio of the donor concentration and the thermodynamic solubility of the API in the same media 80x80mm (600 x 600 DPI)



Graphical abstract 88x35mm (300 x 300 DPI)


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Effect of formulation additives on drug transport through size-exclusion

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