Microstructure of an Immiscible Polymer Blend and Its Stabilization

Article pubs.acs.org/molecularpharmaceutics

Microstructure of an Immiscible Polymer Blend and Its Stabilization Effect on Amorphous Solid Dispersions Ziyi Yang,† Kathrin Nollenberger,‡ Jessica Albers,‡ Duncan Craig,§ and Sheng Qi*,† †

School of Pharmacy, University of East Anglia, Norwich, Norfolk, U.K., NR4 7TJ Evonik Röhm GmbH, Kirschenallee, 64293 Darmstadt, Germany § School of Pharmacy, University College London, London ‡

S Supporting Information *

ABSTRACT: This study proposes use of the phase separation of immiscible polymer blends as a formulation approach to improve the stabilization and solubilization of amorphous molecular dispersions of poorly soluble drugs. This approach uses the phase separation and different drug solubilization properties of the two immiscible polymers in the blend to optimize drug loading and stabilization. The model system tested in this study is a EUDRAGIT E PO-PVP-VA 50/50 (w/w) blend loaded with felodipine via hot melt extrusion. The phase separation behavior of the polymer blend and drug loaded polymer blend formulations were characterized using a range of thermal (MTDSC), spectroscopic (ATR-FTIR), and imaging (AFM and thermal transition mapping) techniques. The polymer blend formulations demonstrated superior performance in drug release as well as stabilization against stressed temperature, stressed humidity, and mechanical milling in comparison to the drug−polymer binary systems. This is attributed to the configuration of the phase separated microstructure of the polymer blend formulations where the hydrophilic polymer domains host high concentrations of molecularly dispersed drug which are protected from moisture induced recrystallization on aging by the hydrophobic polymer domains. Additionally drug incorporation as a molecular dispersion in different polymer phases reduces the drug recrystallization tendency on aging under high temperatures and during milling. KEYWORDS: amorphous, crystallization, phase separation, polymer, surface

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INTRODUCTION Solid dispersion has been used as a formulation approach to modify the physical properties of drugs, for example, increasing the dissolution rate of poorly soluble drugs and the physical stability of amorphous drugs.1−4 In the case of improving the efficacy of delivering poorly soluble drugs, amorphous solid dispersions with the drug being molecularly dispersed in the polymer matrix have been recognized as one of the most effective formulation strategies available.5−8 The formation of a physically stable molecular dispersion requires a certain level of miscibility between the drug and the polymer used. The miscibility is maximized if the drug and polymer are structurally compatible and are able to form intermolecular interactions such as hydrogen bonding.9−11 Other factors that can contribute to form a stable amorphous molecular dispersion include the viscosity and hydrophobicity of the polymer, the © XXXX American Chemical Society

intrinsic stability of the amorphous drug, and the thermodynamic properties of the polymer such as glass transition temperature. Many pharmaceutical polymers containing hydrogen donor/ acceptor groups (such as hydroxyl, amide, and carboxyl groups) have shown a good ability to form hydrogen bonds with drug molecules that also contain acceptor/donor groups.9−11 The formation of drug−polymer interactions often can play an active role in enhancing the physical stability and drug dissolution rate of the solid dispersions.12,13 However some of these polymers such as polyvinylpyrrolidone (PVP) are Received: April 9, 2013 Revised: May 11, 2013 Accepted: May 13, 2013

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dx.doi.org/10.1021/mp400209w | Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Molecular Pharmaceutics

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with the model drug improves the drug−polymer interaction and allows high drug loading in the hydrophilic domains. This will have a direct, positive effect on increasing drug release, as well as reducing the crystallization tendency of the drug during aging and milling of the dispersion. Blending hydrophilic polymers (with high hygroscopicity) with hydrophobic polymers, which do not take up significant amounts of moisture, can increase the overall hydrophobicity of the formulation and reduce the tendency to absorb moisture, thus improving the long-term physical stability under stressed humidity conditions. The illustration of the design of the formulation at a microscopic level is shown in Figure 1. This

highly hygroscopic, which can increase the risk of significant levels of moisture uptake, particularly under stressed humidity conditions, and lead to physical instability with aging. Hydrophobically modified analogues/copolymers of these polymers (such as PVP in comparison to its copolymer PVPVA) have been developed to reduce the hygroscopicity of the material, but the structural modification often weakens the strength of drug−polymer interaction.14 This will affect the physical stability and performance of the formulations. In the present study, we propose to employ polymer blends instead of using a single polymer to improve the physical stability and enhance the performance of drug loaded amorphous molecular dispersions. Polymer blends have a wide range of industrial applications and are a highly cost-effective approach to develop and broaden the application of polymeric materials.15,16 In fact the use of synthetic and natural polymer blends for biomedical applications has been rapidly flourishing in the past three decades.17,18 For example, in the field of drug delivery, polymer blends have been widely studied for controlled release film coatings.18−20 However, there are few studies that have reported the use of polymer blends as the solid dispersion matrix for the delivery of poorly water-soluble drugs.21−25 Similar to drug−polymer dispersions, polymer blends can be homogeneous or heterogeneous depending on the miscibility of the two polymers. If two polymers are completely miscible, a homogeneous blend can be obtained. If the two polymers are partially miscible or immiscible, the blend will typically be heterogeneous after processing with phase separated domains.15,16,26−28 The properties of the interface between the phase separated polymer domains can have a significant effect on the physical properties of the blend. In general, if the two polymers are immiscible, the blend will have a sharp and clear interfacial boundary of the phase separated domains which may lead to an increase in brittleness of the material compared to single polymer alone.29−31 However, if the polymers are partially miscible, the interface between the polymer domains is more diffused and provides better resistance to mechanical stress, such as milling during pharmaceutical processing.32,33 As the physical and mechanical properties of an immiscible blend are directly associated with the phase separated domains, changing the size and morphology of the domains can have a significant impact on the mechanical properties of the blend material.34 The size and morphology of the domains are affected by the composition of the blend and the processing conditions. For an immiscible polymer blend, the morphology of the phase separated domains can change from isolated spherical shapes to interconnected islands by altering the ratio between the two polymers close to 50:50.29−31 Furthermore, by processing the blend under biaxial stress, such as air-blowing, the domains can change to flat layers instead of spherical-shaped domains of one polymer in the other. If the blend is processed under onedirectional stress, such as hot melt extrusion, the domains are likely to be rod-shaped and act as a fibrotic composite in the blend. These rod-shaped domains can reinforce the mechanical stress-bearing capacity in the direction of the rod-shaped domains.34−36 In this study, use of an immiscible polymer blend to enhance the physical stability of hot melt extruded solid dispersions against humidity and temperature stress as well as mechanical stress (milling) was tested. The hypothesis is that the incorporation of hydrophilic polymer with good miscibility

Figure 1. Schematic illustration of the microstructure of the immiscible polymer blend formulation loaded with model drug.

hypothesis was tested using a blend of two model polymers, EUDRAGIT E PO (an ionic polymer which is soluble below pH 5) and PVP-VA (hydrophilic model polymer). These two polymers are largely immiscible, and the model drug felodipine is anticipated to have different solubilities within them.37,38 As the two polymers are largely immiscible, the microstructure of the blend solid dispersion is expected to have continuous and dispersed polymer phases as micrometer-sized or nanosized domains with different amounts of drug molecularly dispersed within them.

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MATERIALS AND METHODS Materials. Felodipine and EUDRAGIT E PO were obtained from Evonik Rohm Co. KG Darmstadt Germany as a generous gift. Kollidon VA 64 (PVP-VA) was donated by BASF, Ludwigshafen, Germany. All reagents used for preparing dissolution media were purchased from Sigma (Gillingham, U.K.) and were of analytical grade. Preparation of Hot Melt Extrusion. Hot melt extrusion was carried out using a Thermo Scientific HAAKE MiniLab II (Thermo Scientific, U.K.) equipped with corotating twin screws. Crystalline felodipine and EUDRAGIT E PO powder with ratios of 10:90, 30:70, 50:50, and 70:30 (w/w) and polymer blend systems of crystalline felodipine, EUDRAGIT E PO, and PVP-VA with ratios of 10:45:45, 30:35:35, 50:25:25 and 70:15:15 were premixed in mortar and pestle before melt extrusion. The barrel temperature was set at 150 °C during extrusion with a dwell time of 5 min. The rotating speed of the twin screws was set at 100 rotations/min. A die of round shape with a diameter of 2 mm was attached to the extruder. The melt extrudates of felodipine−EUDRAGIT E PO and felodipine− B



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scanning angular range was from 3 to 80° (2θ) with a step size of 0.01°, and time per step was 0.5 s. Attenuated Total Reflectance-Fourier Transformed Infrared Spectroscopy (ATR-FTIR). Infrared spectroscopy study was performed on the IFS 66/S FTIR spectrometer (Bruker Optics Ltd., Coventry, U.K.) equippped with a Golden Gate ATR accessory. The crystal is a single reflection diamond element. For each sample, 32 scans were taken with a resolution of 2 cm−1. Scanning Electron Microscopy (SEM). The strand form extrudates were sputter coated by Au/Pd. A JSM 4900 LV SEM (JEOL Ltd., Tokyo, Japan) was used to take images of the surface morphology of the extrudates. Atomic Force Microscopy (AFM). AFM images were acquired in tapping mode at room temperature on a melt extrudate of EUDRAGIT E PO-PVP-VA (50:50 w:w) using a Caliber AFM (Veeco Instruments, Santa Barbara, CA, USA) equipped with a silicon cantilever (AC-160TS, Asylum Research, Santa Barbara, CA, USA). The spring constant of the probe was 42 N/m with an oscillation frequency of 300 kHz at an amplitude of 2.5 V. For each sample scan topography and phase images were acquired. Localized Nanothermal Analysis (NanoTA) and Thermal Transition Mapping (TTM). A novel localized nanothermal based technology known as the VESTA (Anasys Instruments) was used to investigate phase separation within polymer blend extrudates. This is basically a localized nanothermal analysis (nanoTA) technology based on an atomic force microscope (AFM). The principle of this analytical technique is described elsewhere.39,40 The probe was calibrated for temperature by supplying a scanning voltage profile while in contact with polymeric materials with known melting points (poly(ϵ-caprolactone) with Tm at 60 °C, polyethylene with Tm at 130 °C, and polyethylene terephthalate with Tm at 238 °C). The occurrence of a thermal event is defined as penetration of the probe into the sample surface due to softening of the material. However, instead of imaging by AFM, the sample is imaged with an optical microscope to select a tested area. The detected transition temperatures by nanoTA within that area are assigned a color based on a particular palette, and hence the image is assembled based on different transition temperatures. This thermal based imaging method is known as thermal transition mapping (TTM).38 After each measurement the probe was retracted and moved to the next location. All nanoTA measurements were carried out at a heating rate of 10 °C s1−. In Vitro Dissolution Testing. Dissolution testing was carried out on a Copley CIS 8000 dissolution bath (Copley Scientific, U.K.). The withdrawn solution was measured by Perkin-Elmer series 200 HPLC equipped with a UV/vis detector and an autosampler (PerkinElmer LTD, U.K.). The mobile phase was composed of methanol:acetonitrile:water (50:15:35). The column was ODS C18 column (150 mm × 4.6 mm, 5 μm) (SUPELCO INC, Bellefonte, PA, USA). The flow rate of the mobile phase was 1.0 mL/min. The wavelength used was 363 nm. Strand form extrudates of freshly prepared felodipine−EUDRAGIT E PO, felodipine−PVP-VA, and felodipine−polymer blend systems were milled before dissolution testing by mortar and pestle, and the particle size was controlled by sieve to between 63 and 106 μm. Drug release from formulations was tested under nonsink conditions (0.1 M HCl). The paddle method with a speed of 100 rpm was

polymer blend systems with all drug loadings were stored under 75% RH at room temperature and 23% RH at 40 °C, respectively, up to 6 months. The extrudates were milled for 5 min using a ball mill prior to the physical tests and dissolution. The milled extrudates with 63−106 μm particle size were used for all tests. Mechanical Milling of Melt Extrudates. To compare the physical stability against mechanical milling between melt extrudates of felodipine−EUDRAGIT E PO and felodipine− polymer blend systems, both systems with 70% w/w drug loading were milled using a Retsh MM400 ball miller (RETSH, Haan, Germany). Samples were milled for 60 min at a frequency of 30 Hz by a single 7 mm stainless steel ball. Milled samples were tested by MTDSC and ATR-FTIR spectroscopy immediately after milling. Modulated Temperature Differential Scanning Calorimetry (MTDSC). A Q-2000 MTDSC (TA Instruments, New Castle, DE, USA) was used for the MTDSC study. Indium, tin, and n-octadecane were used as the calibration standards for the temperature calibrations. Aluminum oxide sapphire was used for heat capacity calibration for modulated mode. The modulation parameters used were ±0.318 °C/60 s with a 2 °C/min underlying heating rate. A nitrogen purge at a flow rate of 50 mL/min was used. All samples were tested in TA standard crimped pans. For each sample, measurements were repeated three times (n = 3). Dynamic Vapor Sorption (DVS). A Q-5000 SA dynamic vapor sorption (TA Instruments, New Castle, DE, USA) was used for the humidity study. EUDRAGIT E PO raw powder had particle size of D90 smaller than 20 μm, PVP-VA raw powder had particle size of D90 smaller than 50 μm, and a physical mixture (50:50) of these two powders was exposed to a humidity of 75% RH at 25 °C in the DVS for up to 10 h (isohumic test). Hot melt extrudates of 10% felodipine− EUDRAGIT E PO, 10% felodipine−PVP-VA, and melt extrudates of the polymer blend (50:50 w:w) without drug were milled by ball milling for 5 min. The particle size of the milled extrudates was controlled by sieve to 63 to 106 μm. Milled extrudates were tested by DVS with the same procedure. Solubilizing Effect of Polymers on the Crystalline Drug. The impact of polymers on the solubility of crystalline felodipine in 0.1 M HCl was investigated. Different amounts of EUDRAGIT E PO or PVP-VA powders were dissolved in 0.1 M HCl solution, to prepare polymer−HCl solutions with concentrations from 0.004 to 0.038 g/mL (saturated for EUDRAGIT E PO but not for PVP-VA). Physical mixtures of the polymer blend (with ratio of 50:50 w:w in each sample) were dissolved in 0.1 M HCl to prepare solutions with the same concentrations as single polymer−HCl solutions. Excess amounts of crystalline felodipine were added into these solutions and were vigorously stirred for 72 h. The concentrations of felodipine in the different filtrated solutions were then determined using a Lambda XLS UV spectrometer (PerkinElmer LTD, U.K.) at 363 nm wavelength. Powder X-ray Diffraction (PXRD) Study. PXRD studies were carried out at room temperature on a Thermo-ARL Xtra diffractometer (Thermo Scientific, U.K.). Strand form melt extrudates were premilled by mortar and pestle before the tests. Powder form samples were transferred into sample holders with a zero background and placed onto a spinner stage. The X-ray source used was Cu Kα1 with a voltage of 45 kV and current of 40 mA. It was mounted with the wavelength of 1.54 Å. The C



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Figure 2. (a) DSC thermograms of the polymer blend formulations without drug that have EUDRAGIT:PVP-VA ratios from 90:10 (top) to 10:90 (bottom). (b) Plot of ΔCp at the two Tgs of each blend against the percentage of PVP-VA in the blend.

employed, and 900 mL of media at the temperature of 37 °C was used.

immiscibility of the two polymers. If the polymers are highly immiscible, the heat capacity change at the two separated Tgs should be proportional to the intrinsic ΔCp values at Tg of each pure polymer and a linear correlation should be observed between the ΔCp values at the Tg of each polymer in each blend. This is the case for both PVP-VA and EUDRAGIT E PO as seen in Figure 2b. The ΔCp value of each polymer in the blends is linearly proportional to the ΔCp of the pure polymer. This again confirms that the two polymers are highly immiscible. The spatial dimensions of the phase separation in the hot melt extruded polymer blends were visualized using AFM phase imaging and nanothermal imaging (TTM). As seen in Figures 3a and 3b, the AFM phase image of the blends is dominated by the long rod morphology of the phase separated domains dispersed in the continuous phase. The different phases (with different color contrast) observed in the phase image are not identical to the ones observed in the topography image, suggesting that the roughness of the sample has little interference on the features of the AFM phase image. The

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RESULTS AND DISCUSSION Phase Behavior of Polymer Blends. The phase behavior of the blends of PVP-VA and EUDRAGIT E PO was first investigated using MTDSC to determine the Tgs of the polymers, which provides an indication of the degree of phase separation. The physical mixes of the two polymers with ratios of EUDRAGIT E PO:PVP-VA from 10:90 to 90:10 were heated to 140 °C and cooled to 20 °C in order to mix the two phases. After thermal mixing in the DSC pans, each blend was tested using MTDSC. Two distinct Tgs at ca. 50 and 107 °C can be seen in all polymer blends with ratios from 10:90 to 90:10 EUDRAGIT E PO:PVP-VA (Figure 2a), which correspond to the Tgs of the pure EUDRAGIT E PO and PVP-VA, respectively. This indicates the high level of immiscibility between the two polymers without external processing/mixing. The heat capacity changes at the Tg transitions of the blends were further analyzed to confirm the D



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Figure 3. (a) AFM topography and (b) phase image of the 50:50 EUDRAGIT E PO-PVP-VA polymer blend extrudates. (c) TTM images of these polymer blend extrudates and the corresponding nanothermal transition profiles of 12 selected data points at the bottom of the TTM map. (d) Schematic illustration of the microstructure of the EUDRAGIT E PO-PVP-VA blend.

the polymer. However, there are some areas with softening temperatures between 65 and 85 °C, seen with yellow to green color in the thermal mapping. These areas are likely to be partially miscible regions of the two polymers. These intermediate Tgs were not observed in the DSC thermally mixed blends. It is likely that the high temperature and shear stresses melt extrusion process promotes a more intimate mixing between the two polymers, and results in a small amount of molecularly mixed polymer. The low quantity of these miscible phases still suggests that the polymers are highly immiscible. Using the Fox equation (1/Tmix = x1/Tg(polymer1) + (1 − x1)/ Tg(polymer2)), the percentage of the two polymers in these partially miscible phases can be roughly estimated.41 With a Tg of 65 °C, there should be approximately 63% EUDRAGIT E PO and 37% PVP-VA. For the regions with a Tg of 85 °C, there should be nearly 30% EUDRAGIT E PO and 70% PVP-VA. It

proportion of the areas covered by the two phases with distinct physical property differences seen in the AFM phase image can be estimated by the histogram (see Figure 1 in the Supporting Information) of the image, and the ratio of the two phases is close to 50:50. However, it is difficult to assign the chemical nature of the phases. Therefore, nanothermal imaging, TTM, was used to characterize the two phases. The TTM results show a clear distribution of thermal softening transitions, corresponding to the different phases. The thermal mapping of both surface and cross section sides (data not shown) of the extrudates showed a similar pattern. In Figure 3c the continuous phase has a higher softening temperature, which is around 100−110 °C. This is the temperature range of the glass transition temperature of PVPVA, indicating that PVP-VA is the continuous phase. The EUDRAGIT E PO domains have softening transitions between 40 and 50 °C, which agrees well with the DSC measured Tg of E



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Figure 4. (a) Reversing signal of MTDSC data of the freshly prepared polymer blend extrudates with drug loadings from 10 to 70%. (b) Partial ATR-FTIR spectra of the freshly prepared polymer blend dispersions with 50% drug loading demonstrating the molecular interaction of the polymers with the drug.

with 70% drug loading, the high quantity of drug brings the Tg of the PVP-VA phases down to a similar temperature to the Tg of the EUDRAGIT E PO phases, thus only a single Tg transition is observed. Using the Tg temperatures, it is possible to roughly estimate the amount of felodipine molecularly dispersed in each polymer phases using the Fox equation.41 The calculated results are summarized in Table 1. It can be seen that, with increasing the total drug loading, more drug partitioned into the PVP-VA phase rather than the EUDRAGIT

is also noted that in Figure 3c most of the blue EUDRAGIT E PO regions are surrounded by green regions. This indicates that the polymer domains are partially interconnected but largely immiscible, and their microstructure is illustrated in Figure 3d. Phase Behavior of Hot Melt Extruded Drug−Polymer Blend. The solid solubilities of the model drug, felodipine, in EUDRAGIT E PO and PVP-VA were estimated using the previously reported melting point depression method.42,43 The detail of the calculation is described elsewhere, and readers are directed to these references for the detailed methodology.42,43 The calculated solid solubilities of felodipine in EUDRAGIT E PO and PVP-VA are 30.7% and 41.7%, respectively. A polymer blend with a 50:50 ratio of the two polymers was used to load with felodipine. After felodipine incorporation, the molecular interactions between drug and polymers were studied using MTDSC and ATR-FTIR spectroscopy. The MTDSC results of the freshly prepared polymer blend extrudates with drug loadings from 10 to 70% (w/w) are shown in Figure 4a. The clear phase separation of the polymer domains with drug is demonstrated by the clearly separated Tgs, with the exception of the formulation with 70% drug loading. For the extrudates

Table 1. Calculated Drug Distribution of Felodipine in Different Polymer Domains Using the DSC Results Wfelo (w/w) (%)

F

polymer blend systems (w/w) (%)

in E PO

in VA 64

ratio of Wfelo in E PO to Wfelo in VA 64

10 30 50

3.73 7.24 9.96

6.27 22.76 40.04

1:1.68 1:3.14 1:4.02



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Figure 5. DVS results of the polymer alone (as received powder form), the physical mixture of the polymers, and the freshly prepared hot melt extrudates of the polymer blend with and without felodipine (10% w/w drug loading).

caused by the slow diffusion of the moisture into the extrudates as the overall hydrophobicity of the surface of the extrudates is increased by blending with EUDRAGIT E PO, which will slow diffusion of moisture into the continuous hydrophilic PVP-VA domains. After the incorporation of the drug at 10% (w/w), the moisture uptake of the felodipine−PVP-VA extrudates is around 10.8% (w/w) when the equilibrium has been reached. For the felodipine−EUDRAGIT E PO extrudates, the moisture sorption further decreases from EUDAGIT E PO alone to 0.85% after 600 min of isohumic testing. The felodipine− polymer blend extrudates only show 3.3% total moisture uptake after 600 min, which is intermediate between the felodipine− EUDRAGIT E PO and felodipine−PVP-VA formulations. It was noted that, similar to the HME polymer blend placebo at 600 min, the uptake of the felodipine−EUDRAGIT E PO and felodipine−polymer blend extrudates also shows a gradual increase in moisture uptake at extremely slow rates, which may also be a result of the slow diffusion of moisture into the extrudates. The moisture sorption profiles of the PVP-VA powder, physical mixes of PVP-VA and EUDRAGIT E PO, HME polymer blend placebo, and felodipine−EUDRAGIT E PO extrudates all fit well with a Fickian diffusion model with different diffusion coefficients (data not shown). This indicates that in these systems the moisture uptake is dominated by the diffusion mechanism, but with extremely different rates of moisture uptake. This difference is likely to be caused by the difference in the microstructure of the two samples. As suggested earlier in Figure 3, the HME blend placebo consists of rod-shaped micrometer to submicrometer domains of EUDRAGIT E PO in PVP-VA matrix. As moisture diffuses much faster in the hydrophilic polymer domains, the phase separation can lead to a distorted diffusional path length, thus the time to reach equilibrium takes a much longer time than for the physical mix. Drug Solubilization and Dissolution. It is well-known that the addition of polymer to the dissolution media often can enhance the solubility of some poorly soluble drugs.44,45 As seen in Figure 6, the solubility of felodipine increases with

E PO phase. This indicates a higher miscibility of felodipine with PVP-VA than EUDRAGIT E PO. The polymer−drug interactions were further studied using ATR-FTIR spectroscopy. As seen in Figure 4b, the ATR-FTIR spectrum of the blend formulation with 50% drug loading has all the key features from the felodipine−PVP-VA and felodipine−EUDRAGIT E PO spectra. Fourier self-deconvolution (FSD) was used to analyze the N−H region of the IR spectra of the polymer blend containing 50% drug in an attempt to separate the peaks belonging to felodipine−PVP-VA and felodipine−EUDRAGIT E PO domains. The reason for choosing the N−H peak is that this peak is unique to felodipine and absent in the polymer spectra. Therefore it can be used to analyze the presence of the drug as well as distinguish the amorphous and crystalline forms of the drug. However, it was not possible to completely separate the joint peak into two peaks, thus quantitative analysis cannot be performed. Moisture Uptake of Hot Melt Extruded Drug− Polymer Blends. PVP-VA has a higher glass transition temperature, but also a significantly higher hygroscopicity, than EUDRAGIT E PO. Therefore, moisture uptake by the polymer can occur under 25 °C/75% RH aging environment, which will lower the Tg of the system and potentially lead to physical instability. The anticipated advantage of a polymer blend is to increase the overall hydrophobicity of the surfaces, protecting the hydrophilic domains under the highly humid conditions, and reduce moisture uptake by the formulations. The moisture uptake capabilities of the formulations were tested using isohumic tests (a type of test that is programmed to keep the humidity and temperature of the sample chamber constant during the tested period) at 25 °C/75% RH, and it can be seen in Figure 5 that PVP-VA alone can absorb 16.8% (w/w) moisture whereupon equilibrium was reached, whereas EUDRAGIT E PO only absorbs less than 1.3% (w/w) under 25 °C/75% RH. The 50:50 physical mixture of the two polymers takes up approximately 9% (w/w), which is about half of the amount for PVP-VA. This value is reduced to 4.1% (within 600 min) after the hot melt extrusion of the two polymers. It was also noted that, following extrusion, even after 600 min an equilibrium plateau had not been not reached. This may be G



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Figure 6. The solubilities of felodipine in aqueous solutions (pH 1.2) containing PVP-VA, EUDRAGIT E PO, and the blend of the two polymers (50:50) against polymer concentration at 25 °C.

increasing the EUDRAGIT E PO concentration in the HCl media up to a plateau drug concentration of 200 μg/mL. EUDRAGIT E PO concentrations at and above 0.02 g/mL all enable this maximum drug concentration to be obtained. PVPVA shows very little solubilization effect on crystalline felodipine in HCl. The physical mix of the polymers dissolved in the HCl media shows linear solubilization enhancement of crystalline felodipine, which can reach 155 μg/mL with a polymer concentration of 0.038 g/mL. This is more than a 200fold increase in comparison to the solubility of crystalline felodipine alone in HCl (which is 0.69 μg/mL). The drug release profile of the freshly prepared polymer blend extrudates with 10% drug loading shows the most significant enhancement in dissolution, in comparison to the binary felodipine−EUDRAGIT E PO and felodipine−PVP-VA formulations (Figure 7). However, with increasing the drug loading to 30% and above, the drug release pattern shows little difference between the binary and polymer blend formulations. It is also noted that the formulations with 10% drug loading can rapidly reach supersaturation as indicated by the significant reduction of cumulative drug release within 60 min. The degree of supersaturation of the 10% formulations is higher in the polymer blend extrudates than the binary formulations. A possible explanation of the similar release patterns of 30−70% drug loaded formulations is that a significant decrease of the surface wettability of the samples, caused by the high level of drug incorporation, slows down the dissolution process. Stabilization Effects of Polymer Blend Formulations. In order to individually establish the stabilization effect of the polymer blend in comparison to the corresponding binary solid dispersions against stressed temperature and humidity, the HME formulations were first aged under separate conditions, 40 °C/23% RH (high temperature) and room temperature/ 75% RH (high humidity). EUDRAGIT E PO has a Tg of 45 °C, and felodipine has a Tg of approximately 48 °C. Thus the Tg of a molecular dispersion of felodipine and EUDRAGIT E PO should still be around 45 °C. Therefore aging at 40 °C, which is close to the Tg of the polymer−drug dispersion, may induce physical instability via increasing the molecular mobility of the system.46−48 The use of a polymer blend can reduce the drug load in the EUDRAGIT E PO phase with low Tg by molecularly incorporating a certain proportion of the drug

Figure 7. Drug release results of freshly prepared (a) felodipine− EUDRAGIT E PO dispersions, (b) felodipine−PVP-VA dispersions, and (c) felodipine−polymer blend HME dispersions.

into the polymer domains with higher Tg, so as to miminize the amount of drug that can be affected by the temperature stress in the formulations. It can be seen in Figure 8 that, for both high humidity and high temperature stress conditions, the polymer blend formulations show little change in the Tg values obtained in comparison to the fresh samples (Figure 4a). a. Against Stressed Humidity. The blend extrudates show a much lower level of surface crystallization after 1 month of aging at room temperature/75% RH in comparison to the binary felodipine−EUDRAGIT E PO and felodipine−PVP-VA formulations. This is particularly evident in the formulations with high drug loadings (70% w/w), as seen in Figure 9. Quantitatively, the amount of drug crystallization was estimated using the melting enthalpy of felodipine in the DSC results of the aged samples. It can be seen in Figure 10a that there is no H



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Figure 8. MTDSC reversing heat capacity signals of aged felodipine−polymer blend solid dispersions aged under 40 °C/23% RH and room temperature/75% RH for 6 months.

Figure 9. SEM images of the surfaces of 70% drug loaded extrudates after 1 month aging under 75% RH at room temperature: (a) felodipine− EUDRAGIT E PO, (b) felodipine−PVP-VA, and (c) felodipine−polymer blend.

months aging at room temperature/75% RH. The broad recrystallization exotherm prior to the melting suggests the likelihood of the presence of some amorphous drug domains which readily recrystallize on heating during DSC tests. The presence of crystalline felodipine in both 70% drug loaded EUDRAGIT E PO and PVP-VA extrudates was confirmed by the ATR-FTIR results of the aged extrudates. As seen in Figure 11, the crystalline felodipine N−H peak can be clearly seen at 3365 cm−1 in both aged formulations, but not in the spectrum of aged drug−polymer blend formulation. This indicates that felodipine is preserved as molecular dispersion in the blend formulation. The low level of moisture uptake of the polymer blend extrudates under high humidity (as seen in Figure 5) may contribute to the observed low level of drug crystallization following aging under humidity. b. Against Stressed Temperature. Similar to the stressed humidity condition results, no obvious evidence of crystallization can be seen in the aged polymer blend samples (with 70% drug loadings) at 40 °C/23% RH by either MTDSC (Figure 8 and 10) or ATR-FTIR (Figure 11) spectroscopy methods. However, the binary felodipine−EUDRAGIT E PO formulations show an obvious crystalline felodipine melting in the DSC results and the appearance of the crystalline N−H

DSC detectable melting of felodipine in the 1 month aged drug−polymer blend and drug−PVP-VA extrudates, despite the observation of a low level of surface crystallization. This could be a result of either the total amount of drug crystallization being below the detection limit of the DSC or dissolution of the crystalline drug into the softened polymer on heating prior to the melting of the drug. However, the aged felodipine− EUDRAGIT E PO formulations show a melting accompanied by the endothermic shoulder peak and a broad recrystallization exotherm prior to the appearance of the endothermic shoulder peak. The main melting transition is observed at 139 °C. The melting of the crystalline felodipine polymorph I is about 145 °C, and the melting of crystalline felodipine in EUDRAGIT E PO as physical mixture is around 140 °C (data not shown). This transition is likely to be the depressed melting of felodipine polymorph I in EUDRAGIT E PO. For a rough estimation, the enthalpy of the melting peak was used to calculate the percentage of crystallized drug in the formulation (calculated by dividing the totally enthalpy of melting of pure crystalline felodipine polymorph I using the measured enthalpy of the melting peak appeared in the DSC curve of the extrudates Wcrys % = (ΔHextrudate/ΔHdrug) × Wdrug loading), which was around 0.49% (w/w). This value increased to 1.31% after 6 I



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Figure 10. (a) DSC results of the HME solid dispersions with 70% drug loading during aging for 6 months under 40 °C/23% RH and room temperature/75% RH. (b) The kinetic profile of felodipine crystallization in the 40 °C/23% RH aged binary felodipine−EUDRAGIT E PO HME extrudates with 70% drug loading.

Figure 11. ATR-FTIR spectra of 70% drug loaded extrudates after 1 month and 6 months aging under different conditions.

peak at 3365 cm−1 after 6 months aging. The kinetic process of felodipine recrystallization in the binary felodipine−EUDRAGIT E PO system aged under stressed temperature was studied. The crystallization process shown in Figure 10b does not fit the classic Avarim sigmoidal profile,49 lacking the nucleation phase (initial nucleation phase with slow rate) before the takeoff of the measurable crystallization growth stage. This indicates that the crystalline nuclei may already be present in the freshly

prepared 70% drug loaded binary samples. As the polymer blend formulation shows no detectable melting of felodipine in the aged samples, this implies that the drug is better solubilized in the blend formulation in comparison to the binary systems. This confirms the hypothesis that the involvement of PVP-VA facilitates the solubilization of felodipine in the polymer blend. The drug release profiles of all formulations aged under both conditions are very similar to the freshly prepared samples (see J



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Figure 2 in the Supporting Information). This may seem to contradict the observation from the SEM, DSC, and ATR-FTIR results, as all other methods suggest at least the presence of surface crystallization. However, an important consideration is that all dissolution experiments were performed on milled powders of the extrudates. After milling, the effect of surface crystallization of the intact extrudates on dissolution is dramatically reduced as the inner core of the extrudates is exposed to the media in the form of small particles. This could contribute to the insignificant changes in the dissolution behavior observed of the aged samples. The polymer blend formulations showed better dissolution performance than the corresponding felodipine−EUDRAGIT E PO and felodipine− PVP-VA formulations. c. Against Mechanical Milling. The stabilization capability of the polymer blend formulation against mechanical stress was also tested. It was observed that, within 5 min of milling, crystalline felodipine can already be detected in freshly prepared felodipine−EUDRAGIT E PO extrudates with 70% drug loading (data not shown). In this study, the milling time was increased to 60 min in order to maximize the mechanical stress. It can be seen in Figure 12 that the PXRD results clearly indicate the presence of a significant amount of crystalline felodipine polymorph I in the felodipine−EUDRAGIT E PO

formulations after 60 min of milling. Both felodipine−PVP-VA and felodipine−polymer blend show little evidence of the presence of crystalline drug in the milled samples. The DSC results of all milled samples show three thermal events, glass transition, exothermic transition (either polymorphic transition or recrystallization), and melting. The melting transition of the milled felodipine−EUDRAGIT E PO samples is observed at 138 °C. It has a much larger enthalpy than those of the melting peaks of the blend formulation and the felodipine−PVP-VA samples. The melting is identical to the melting transition of crystalline felodipine polymorph I in the physical mixture of felodipine−EUDRAGIT E PO with ratio of 70:30 (w/w) (data not shown). Therefore it is reasonable to suggest that this is the melting of crystalline felodipine polymorph I in the milled sample which may either be present before the DSC test or be generated during the heating of the DSC run. The milled felodipine−EUDRAGIT E PO samples also show a clear exothermic peak at approximately 97 °C (peak temperature). This is very close to the recrystallization exotherm of amorphous felodipine, and so it is likely that the total melting at 138 °C is contributed to by the melting of both crystalline felodipine generated during the milling process and some recrystallized polymorph I from amorphous felodipine during the heating of the DSC run (considering both the PXRD and DSC data). The DSC results of both milled felodipine−PVP-VA and the drug−polymer blend extrudates show a broad exothermic transition at higher temperature than the one observed in the DSC result of the milled felodipine−EUDRAGIT E PO samples. This exothermic peak offsets as the melting starts and is highly likely to be the recrystallization of amorphous felodipine generated during milling (not a molecular dispersion of drug in the polymer, but a separate amorphous drug phase). That this transition occurs at a higher temperature may be a result of the improved miscibility between the drug and the PVP-VA in comparison to EUDRAGIT E PO. The melting transitions in the blend and PVP-VA binary systems are both at 136 °C, which is close to the depressed melting of felodipine polymorph I in PVP-VA. However in comparison to the melting enthalpy of the milled felodipine−EUDRAGIT E PO, the melting enthalpy values for felodipine−PVP-VA and the drug−polymer blend extrudates are much lower, indicating a lower level of phase separation created during milling by the incorporation of PVP-VA. These results suggest that the incorporation of PVP-VA can improve the mechanical stress bearing properties of the extrudates and reduce the crystallization tendency of the drug during milling. This can be attributed to the fact that, in the polymer blend, particularly for the extrudates with high drug loadings (70% w/w which is above the drug solubility limit in the polymers), more drug is molecularly solubilized in the blend polymer phases, therefore the formulation has a lower level of supersaturation in the solid state in comparison to the felodipine−EUDRAGIT E PO binary formulation with the same drug loading. This further leads to a lower level of the risk of phase separation and drug recrystallization occurring during milling.

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DISCUSSION Polymer Blend Concept as a Formulation Platform. The proposed formulation concept of this study is to use polymer blends to improve two properties of a conventional binary solid dispersion formulation. They are to increase the solid solubility/apparent solid solubility of drug in the polymer

Figure 12. Effects of 1 h of milling on the formulations loaded with 70% felodipine. (a) PXRD results of the milled samples with the diffraction pattern of crystalline felodipine polymorph I as reference. (b) DSC results of the milled samples with the thermal graph of amorphous felodpine as reference. K



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The disadvantage of the polymer blend approach is that the behavior of the polymer blend alone needs to be well understood prior to formulation development which may prolong the overall formulation development process. However, with the accumulation of knowledge of polymer blend properties, choosing the blend system can be easily rationalized.

matrix, and to enhance the physical stability of the formulation on aging as well as against mechanical stress. The key to the design is the difference in the solid miscibilities of the polymers and the configuration of phase separation of the immiscible polymeric domains loaded with drug (Figure 1). The configuration of the phase separation can be manipulated by changing the ratio of the two polymers and the processing method, and studies focusing on these aspects are still ongoing. Ideally, it is preferable that the dispersed phase has a higher solid solubility and stronger intermolecular interaction with the drug, and the surfaces of the polymer blend extrudates are covered by the more hydrophobic polymer phase in which the drug has a lower solubility. A higher drug solid solubility often brings the advantages of improved stability during aging and mechanical milling. Therefore this designed phase separation brings the benefit for increasing the drug loading while also exhibiting good physical stability. However, most polymers that can form strong interactions with drugs are structurally hydrophilic. These in turn are typically hygroscopic, which is undesirable and reduces physical stability. Blending a hydrophobic polymer with the hydrophilic polymer and the poorly water-soluble drug can reduce the overall hydrophobicity of the formulation and therefore reduce moisture uptake. This proposed formulation concept can potentially have a wide range of applications including loading with multiple drugs and providing controlled release. Although the system used in this study did not achieve the same phase separation configuration as proposed above (as the dispersed phase is EUDRAGIT instead of PVP-VA), the blend formulation still obtained better physical stability than the corresponding binary systems. This suggests that in practice even with this inversed configuration the polymer blend matrix still offers improved stabilization, and the underpinning mechanism behind this is currently under investigation. Advantages and Limitations of Using Polymer Blends for Hot Melt Extrusion. The results from this study demonstrate the advantages of using polymer blends as a solid dispersion carrier over conventional binary polymer−drug dispersions for the delivery of poorly water-soluble drugs. The physical stability and in vitro dissolution can be improved by using an immiscible polymer blend. This is achieved mainly by optimizing the overall physical properties of the blend which “silences” the disadvantages of each polymer. In order to have both good physical stability and a satisfactory drug release profile, the ideal solid dispersion carrier should have good miscibility with the drug in the solid state, be nonhygroscopic, and readily dissolve in gut media. However, most pharmaceutical polymers only have one or two of these essential properties. Therefore, instead of engineering new polymers which will have a long and expensive development and regulatory approval period, developing appropriate polymer blends can be a quick and easy approach in formulation development. For example, in this study EUDRAGIT E PO and PVP-VA were used, which are FDA approved pharmaceutical excipients. Through using them as a blend, the physical instability caused by the hygroscopicity of the PVP-VA can be reduced and its high miscibility with the model drug can be used to benefit the physical stability of formulations particularly with high drug loadings. After blending, the presence of EUDRAGIT E PO can reduce the moisture uptake compared to the pure PVP-VA binary system, as well as facilitate the rapid release in gastric conditions at low drug loading.

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CONCLUSIONS EUDRAGIT E PO alone can stabilize amorphous felodipine with a drug loading up to 50% (w/w) with a level of total recrystallization below 5% under stressed humidity and temperature conditions. By blending with PVP-VA, the polymer blend can dramatically reduce moisture uptake to below 5% (in comparison to 12% uptake of the PVP-VA−drug binary formulation). The polymer blend matrix can stabilize up to 70% amorphous drug with below 2% recrystallization. In addition, using the polymer blend can significantly reduce surface recrystallisation under humidity and the recrystallisation tendency of felodipine in the HME extrudates during milling, which is a commonly used downstream processing method. The stabilization effect of the polymer blend is largely believed to be a result of the phase separated microstructure of the formulation which reduces moisture uptake and increases the miscibility of the drug in the matrix.

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ASSOCIATED CONTENT

S Supporting Information *

Figures depicting AFM tapping mode phase image, histogram of the phase image, and drug release results. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Z.Y. would like to acknowledge the financial support from Evonik during his PhD. The authors would also like to express thanks for the support received from the Interreg IV IDEA project funded by the European Union.

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Microstructure of an Immiscible Polymer Blend and Its Stabilization

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