Triblock Copolymer Blends with

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Anal. Chem. 2005, 77, 3570-3578

Depth Profiling of Poly(L-lactic acid)/Triblock Copolymer Blends with Time-of-Flight Secondary Ion Mass Spectrometry Christine M. Mahoney*

Chemical Science and Technology Laboratory, Surface and Microanalysis Science Division, National Institute of Standards and Technology, 100 Bureau Drive, Mail Stop 8371, Gaithersburg, Maryland 20899 Jinxiang Yu and Joseph A. Gardella Jr.*

Department of Chemistry, State University of New York at Buffalo, Buffalo, New York 14260-3000

Time-of-flight secondary ion mass spectrometry employing an SF5+ polyatomic primary ion source was utilized to obtain a series of in-depth profiles from PLLA/PluronicP104 (poly(ethylene oxide-co-propylene oxide) triblock copolymer) blends in attempts to quantify the in-depth surface segregated Pluronic region. The resultant in-depth profiles were consistent with theoretical models describing the surface segregated region in polymeric blends and copolymer systems, with a surface enriched PluronicP104 region, followed by a P104 depletion layer, and finally a constant composition bulk region. These results were consistent over a range of concentrations (1-25%). The depth profiles obtained using cluster SIMS were compared to information obtained using X-ray photoelectron spectroscopy. The results demonstrate that, with cluster primary ion bombardment, we are for the first time able to quantify the polymeric composition as a function of depth within certain multicomponent polymer blends. This success can be attributed to the sputter characteristics of polyatomic primary ion bombardment (SF5+) as compared to monatomic primary ion beams.

material because the degradation product, lactic acid, is readily metabolized by the body.1,9 The main advantage of these particular materials is that no retrieval of the device is needed after usage. In addition, the degradation rate can be easily controlled through variation of its molecular weight. Because of these benefits, PLLA and its copolymers with poly(glycolic acid) (PGA) have become widely utilized biodegradable polymers for drug delivery and tissue engineering applications with more recent advancements in the field of drug-eluting stents and protein drug delivery.9-19 Poly(ethylene oxide) (PEO) has also been a useful biomaterial for numerous pharmaceutical applications as it is a neutral, highly biocompatible, and pharmacologically inactive water-soluble polymer.1,8,20-27 The incorporation of PEO into biodegradable PLLA-based drug delivery implant systems is expected to improve the interfacial biocompatibility of the polymeric devices as a result of the preferential migration of the PEO component to the surface. In addition, blend matrixes of PEO and relatively hydrophobic PLLA will improve the three-dimensional stability and the biological activity of water-soluble macromolecular drugs such as proteins or enzymes in the delivery systems.1,20-27 This is because the surface segregated PEO components provide a diffusive hydro-

Polymeric biomaterials have widespread use in clinical applications including as surgical implants, absorbable sutures, tissue engineering scaffolds, and drug delivery devices.1-9 Poly(L-lactic acid) (PLLA) has shown particular promise as a biodegradable

(10) Campbell, D. K.; Rogers, M. D. Rev. Cardiovasc. Med. 2002, 3 (5), 10-15. (11) Sokyan, O.; Donovan, M. G. U.S. Pat. 20010000802, 2001.. (12) Fischell, D. R.; Spaltro, J. U.S. Pat. 20040002755, 2004. (13) Calceti, P.; Salmaso, S.; Elvassore, N.; Bertucco, A. J. Controlled Release 2004, 94, 195-205. (14) Rouzes, C.; Leonard, M.; Durand, A.; Dellacherie, E. Colloids Surf., B 2003, 32, 125-135. (15) Singh, S.; Singh, J. Int. J. Pharm. 2004, 271, 189-196. (16) Rahman, N. A.; Mathiowitz, E. J. Controlled Release 2004, 163-175. (17) Park, T. G.; Cohen, S.; Langer, R. Macromolecules 1992, 25, 116-122. (18) England, J. L. J. Undergraduate Sci. 2003, 5 (2), 17-21. (19) Kader, A.; Jalil, R. Drug Dev. Ind. Pharm. 1998, 24 (6), 527-534. (20) Lee, J.-W.; Yu, J.; Gardella, J. A. Jr.; Hicks, W. L. Jr.; Hard, R.; Bright, F. V.; Jeong, E. D.; Chang, T. To be submitted to Langmuir. (21) Andrade, J. D.; Hlady, V.; Jeon, S. I. Adv. Chem. Ser. 1996, 248, 51. (22) Zalipsky, S. Bioconjugate Chem. 1995, 6, 150-165. (23) Nucci, M. L.; Shorr, R.; Abuchowski, A. Adv. Drug Delivery Rev. 1991, 6, 133. (24) Katre, N. Adv. Drug Delivery Rev. 1993, 10, 91. (25) Gaertner, H. F.; Offord, R. E. Bioconjugate Chem. 1996, 7, 38. (26) Delgado, C. Crit. Rev. Ther. Drug Carrier Syst. 1992, 9, 249. (27) Gref, R.; Minamitake, Y.; Perachhia, M. T.; Trubetskoy; Torchilin, V.; Langer, R. Science 1994, 1600.

* To whom correspondence should be addressed. E-mail: [email protected]. Telephone: 301-975-8515. Fax: 301-417-1321. (1) Uhrich, K. E.; Cannizzaro, S. M.; Langer, R. S.; Shakesheff, K. M. Chem. Rev. 1999, 99, 3181-3198. (2) Fournier, E.; Passirani, C.; Montero-Menei, C. N.; Benoit, J. P. Biomaterials 2003, 24, 3311-3331. (3) Seal, B. L.; Otero, T. C.; Panitch, A. Mater. Sci. Eng. R-Rep. 2001, 34 (4-5), 147-230. (4) Luo, Y.; Prestwich, G. D. Expert Opin. Ther. Pat. 2001, 11 (9), 1395-1410. (5) Heller, J.; Barr, J.; Ng, S. Y.; Abdellauoi, D. S.; Gurny, R. Adv. Drug Delivery Rev. 2002, 54 (7). (6) Cui, J. F.; Yin, Y. J.; He, S. L.; Yao, K. D. Prog. Chem. 2004, 16 (2), 299307. (7) Kazanci, M. Mater. Technol. 2003, 18 (2), 87-93. (8) Langer, R.; Tirrell, D. A. Nature 2004, 428, 487-492. (9) Jain, R.; Shah, N. H.; Malick, A. W.; Rhodes, C. T. Drug Dev. Ind. Pharm. 1998, 24 (8), 703-727.

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10.1021/ac048274i CCC: $30.25

© 2005 American Chemical Society Published on Web 04/26/2005

philic layer at the surface, which enables increased interaction between the cellular environment and the polymeric biodevices.1,20,21 In addition to this, PEO serves as a means to protect the hydrophilic macromolecular drugs via encapsulation and formation of micelles.1,20,22-27 Pluronic surfactants are nonionic triblock copolymer surfactants containing alternating PEO and poly(propylene oxide) (PPO) components.28 These block copolymers exhibit a wide range of hydrophilicites as a function of changing PEO/PPO ratio, so that one can expect to obtain different phase-separated morphologies with PLLA as well as different degrees of hydration of the matrix.28,29 When used as drug-releasing matrixes, these PLLA/ Pluronic blends have been proven to extend protein release and minimize the initial protein burst when compared to the pure PLLA homopolymers.18,29 In protein drug delivery devices based on Pluronic/PLLA blends, it is essential to be able to accurately measure the composition both at the surface and as a function of depth, as it is this surface region that is interacting with the biological environment. In addition to this, it is essential to determine the location of the protein or drug in the film because if it is located nearer to the surface, this could potentially result in an initial burst release of protein, which could in some cases be harmful. A means of measuring the surface composition and the extent of preferential segregation of both proteins and polymeric materials to the surfaces of these materials is absolutely essential. The surface chemistry as determined by both X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (TOF-SIMS) of these polymer blend materials has been described in detail in previous work.20 These results have confirmed that there is preferential segregation of the Pluronic surfactant to the surface in these copolymer blends. However, this work was limited to the top 10-100 Å of the surface and does not characterize the full extent of surface segregation that occurs in these systems, nor does it give in-depth compositional information. Though angle-dependent XPS can be used to characterize the compositional gradient that exists in these samples, these data are convoluted and are not a direct measure of the composition as a function of depth. Theoretical models are required to extract such information as well as apriori knowledge about sample concentrations. Until recently, there has not been a method that is capable of directly monitoring the distribution of the various components and additives in polymer blends and copolymers as a function of depth over the range of 10-1000 nm.30 Previous TOF-SIMS characterization of these systems was accomplished using monatomic primary ion beams (e.g., Ar+, Ga+, Cs+), which tend to cause significant subsurface damage particularly in organic and polymer samples. This beam-induced damage coupled with low sputter yields precludes the ability to obtain information as a function of depth in organic and polymer samples. With the advent of polyatomic primary ion beams however (e.g., SF5+, C60+, Au3+, often referred to as “cluster SIMS”), we now have the capability to measure compositional information as a function of depth in certain organic and copolymer systems. When a cluster ion strikes a surface, it is theorized that the cluster (28) BASF website: http://www.basf.com/static/OpenMarket/Xcelerate/ Preview_cid-982931199819_pubid-974236729499_c-Article.html. (29) Park, T. G.; Snadar, C.; Langer, R. Macromolecules 1992, 25, 116-122. (30) Mahoney, C. M.; Gillen, J. G.; Roberson, S. V. Anal. Chem. 2004, 76, 31993207.

dissociates upon impact resulting in each of the constituent atoms having a fraction of the initial energy.31,32 This process results in a reduced penetration depth for the constituent atoms, thus decreasing the subsurface beam induced damage and also increasing the sputter rate (higher number of atoms per impact). These advantages have allowed for the determination of in-depth profiles through organic and polymeric materials for the first time with particular success in biodegradable polymeric materials.30,32-35 We have had success in depth profiling many polymeric biomaterials including poly(lactic) acid, poly(glycolic) acid, poly(lactideco-glycolide), poly(ethylene oxide), poly(propylene oxide), polycaprolactone, poly(methyl methacrylate), poly(hydroxyethyl methacrylate), poly(n-butyl methacrylate), and varying poly(HEMA)s. In this work, we report results from molecular compositional depth profiling of a series of PLLA/Pluronic-P104 blends of varying compositions using SF5+ polyatomic primary ion bombardment. These profiles represent our first successful attempt to quantify the surface segregated region in a polymer blend. In each profile, there was a surface enriched Pluronic-P104 region, followed by a P104 depletion layer, and finally a constant bulk composition region. This was consistent over a range of P104 concentrations (1%-25%). There was also a similar effect occurring in the buried interfacial region (polymer/Si interface). These results are consistent with previous models describing preferential segregation in polymer blend and copolymer surfaces.36-39 These results also demonstrate that, with cluster primary ion bombardment, we are now able to successfully determine the polymeric composition as a function of depth in certain polymeric blends. We anticipate that cluster SIMS will be a useful tool for obtaining in-depth information, both qualitative and potentially quantitative, on inhomogeneities and domain formations that occur in polymeric blends used for biomedical applications. This information can be directly correlated to the performance of the device, helping to further improve the drug development process as well as aid in quality control. EXPERIMENTAL SECTION Sample Preparation. Poly(L-lactide) (molecular weight 100 000) was purchased from Polysciences Inc. (Warrington, PA).40 Pluronic P104 (H2O solubility >10%, molecular weight 5900, PEO 40 wt %) was kindly donated by BASF Corp. (Mount Olive, NJ). Si wafers were cut into 1 cm × 1 cm pieces and cleaned with n-hexane and methanol. HPLC grade chloroform was used for (31) Appelhans, A. D.; Delmore, J. E. Anal. Chem. 1989, 61, 1087-1093. (32) Gillen, G.; Roberson, S. Rapid Commun. Mass Spectrom. 1998, 12, 1303. (33) Wagner, M. S. Anal. Chem. 2004, 76, 1264-1272. (34) Wagner, M. S. Submitted to Surf. Interface Anal. (35) Wagner, M. S. Submitted to Anal. Chem. (36) Chen, X.; Gardella, J. A. Jr.; Ho, T.; Wynne, K. J. Macromolecules 1995, 28 (5), 1635-1642. (37) Zhuang, H.-Z.; Marra, D. G.; HO, T.; Chapman, T. M.; Gardella, J. A., Jr. Macrolmolecules 1996, 29 (5), 1660-1665. (38) Zhao, J.; Rojstacer, S. R.; Chen, J.-X.; Xu, M.; Gardella, J. A., Jr. Macromolecules 1999, 32 (2), 455-461. (39) Mahoney, C. M.; Gardella, J. A., Jr.; Rosenfeld, J. C. Macromolecules 2002, 35 (13), 5256-5266. (40) Certain commercial equipment, instruments, or materials are identified in this article to specify adequately the experimental procedure. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the materials or equipment identified are necessarily the best available for the purpose.

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Figure 1. Positive secondary ion mass spectra of (a) Pluronic P104 surfactant film and (b) PLLA film. Note: boldface type represents the peaks that will be monitored during the depth profile process. Peaks in italics represent PDMS contamination.

the preparation of a series of ∼3% (mg/mL) Pluronic P104/PLLA blend solutions where the ratio of P104/PLLA is varied depending on the desired weight percent. These solutions were spin cast at 2000 rpm for 60 s onto the Si wafers. The films were then dried further in a vacuum oven (National Appliance Co. model 5830 vacuum oven, Portland, OR) under a reduced pressure (∼150 mTorr) for 48 h. Film thickness measurements were made using stylus profilometry (Tencor Instruments R-step 200, Milpitas, CA) employing a 10-mg stylus force. The resulting films analyzed by SIMS in this work contained 1%, 2%, 4%, 5%, 10%, and 25% (by weight) P104. TOF-SIMS Analysis. TOF-SIMS experiments were performed on an Ion-TOF IV (Mu¨nster, Germany) time-of-flight secondary ion mass spectrometer equipped with both Ar+ and SF5+ primary ion beam sources.40 Sputter depth profiling was performed in the dual-beam mode, where two separate guns were utilized for analysis and sputtering. The analysis source was a 10-keV Ar+ beam, which bombarded the surface at an incident angle of 45° to the surface normal. The target current was maintained at ∼2 pA pulsed current with a pulse width of 1 ns and a 150-µs cycle time (∼6666 Hz frequency). Each spectrum was averaged over a 30-s time period with a raster size of ∼200 µm × 200 µm. These conditions resulted in Ar+ ion doses that were well below the static SIMS limit of 1013 ions/cm2. Resulting mass resolutions were typically >3000. The sputter ion source utilized in this work was a 5-keV SF5+ cluster primary ion beam, which bombarded the surface at an incident angle of 45° to the surface normal. The target current was maintained at ∼2 nA throughout the sputter process as measured by a faraday cup. The sputtered area was approximately 1000 µm × 1000 µm. Both positive and negative secondary ions were extracted from the sample into a reflection3572

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type time-of-flight mass spectrometer. The secondary ions were then detected by a microchannel plate detector with a postacceleration energy of 10 kV. A low-energy electron flood gun was utilized for charge neutralization in the analysis mode. The approximate electron dose per analysis was ∼1 × 1020 electrons/ m2. It is expected that any damage from the electron beam is minimal in comparison to primary ion beam damage. XPS Analysis. All XPS measurements were performed on a Physical Electronics PHI 5300 X-ray photoelectron spectrometer (Chanhassen, MN) with a hemispherical analyzer and a singlechannel detector, operated at 15 kV and 20 mA. Samples were irradiated with a Mg KR radiation source (1253.6 eV). The pass energy was 89.45 eV for survey scans and 17.9 eV for highresolution scans. Resolutions of 1.0 and 0.1 eV/step were used for survey scans and high-resolution scans, respectively. The base pressure was maintained at 1 × 10-9 Torr (1.33 × 10-7 Pa) for all experiments. Binding energies were calibrated by setting the CHx peak in the C 1s envelope at 285.0 eV. All measurements were taken at four different photoelectric takeoff angles (15°, 30°, 45°, 90°) corresponding to escape depths from of ∼2.7, 5.0, 7.3, and 10.0 nm, respectively. Curve fitting was performed for each carbon fraction of CHx, CsO, and CdO functionalities using AugerScan Version 2.41 software (RBD Enterprises, Bend, OR). Quantitative analysis was done using the CHx peak to represent the Pluronic P104 fraction of the blend and the CsCdO peak to represent the PLLA portion. RESULTS AND DISCUSSION Reference Spectra of PLLA and P104. The reference spectra for the pure P104 and PLLA films are shown in Figure 1 along with the corresponding chemical structures. Figure 1a

shows the mass spectra taken from a P104 film (∼500 nm) spin cast onto Si. In addition to peaks associated with the Pluronic surfactant (e.g., m/z ) 41, 45, 59, 73, 87, 99, 101, 115, 117),20 there are also poly(dimethylsiloxane) (PDMS) peaks present (m/z ) 28, 43, 73, 147, 191, 207, 221) in this spectrum. This is a commonly observed surface contaminant, and this observation alone shows the utility of SIMS as a surface analysis technique for biomedical applications. Since PDMS has a low surface energy with respect to most other materials, it tends to spread over the surfaces of materials when present, including biomedical devices. Hence, if these devices are placed into the body, the body will initially recognize the device as PDMS, no matter the bulk composition, since it is only the surface that is interacting with the local environment. Figure 1b shows the mass spectrum taken from the pristine PLLA film. Peaks located at m/z ) 43, 45, 56, 87, 89, 100, 128, 143, 145, 200, etc., are consistent with the PLLA fragment peaks observed in earlier work.35 There was no detectable PDMS contamination at the surface of the PLLA film. Certain peaks associated with each component were selected based on their relative intensities as well as their separation from other peaks. These peak intensities were then monitored as a function of increasing SF5+ dose in order to determine if a change in the polymeric composition could be seen as a function of depth using SIMS. The masses chosen to represent the components include m/z ) 128 associated with the (2n - O)+ fragment in PLLA (where n represents a single PLLA monomeric unit) and m/z ) 59 corresponding to both (x + H)+ and (y + CH3)+ in the P104 triblock copolymer (where x and y correspond to PPO and PEO monomers, respectively). Both of these peaks are highlighted in boldface type in Figure 1. Depth Profiles of PLLA/P104 Blends. The positive secondary ion intensities (averaged over 30 s) of m/z ) 59 (P104), 128 (PLLA), and 28 (Si substrate) were monitored as a function of increasing SF5+ primary ion dose for samples containing 100%, 25%, 10%, 5%, 4%, 2%, 1%, and 0% (w/w) P104 in PLLA. Recall that as the SF5+ primary ion dose increases, more material is removed, and thus, there is a direct relationship between the primary ion dose and the sampling depth into the film. The resulting depth profiles of the 25%, 10%, and 5% (w/w) P104 samples are shown in Figure 2. Both absolute (Figure 2a-c) and normalized (Figure 2d-f) secondary ion intensities are shown. In all three samples, significant intensity variations occurred in the surface and interfacial regions. More specifically, we see that where there is an increase in P104 signal (b), there is a corresponding decrease in PLLA signal (2) and conversely, indicating that phase separated domain formations may be occurring at the interfacial regions. These effects were consistently observed even when monitoring different masses selected from the mass spectra in Figure 1 (e.g., m/z ) 100, 145, and 200 for PLLA and m/z ) 115 and 87 for P104). Even after normalizing these profiles to the total ion intensity (see Figure 2d-f), these effects are still present and in some cases more obvious, indicating that these effects are not an artifact of changing total secondary ion yields with increasing primary ion dose. For all three cases, the secondary ion intensities of both the PLLA and P104 peaks remain stable with increasing SF5+ dose right up to the interfacial region where the signal intensities drop with a corresponding increase in the Si intensity (9). The curves

for the normalized intensities tend to be more flat, indicating that there is a minor variation in the total secondary ion yield with depth. The fact that the difference between the normalized and absolute intensity profiles is slight illustrates the well-behaved nature of these particular films under polyatomic primary ion bombardment (e.g., beam-induced degradation effects are minimal). This stability in secondary ion yields as a function of increasing SF5+ polyatomic primary ion dose has rarely been observed in other polymeric films.33,34 This result is particularly exciting because of the thickness of the films, which on average vary from ∼600 to 900 nm. We have successfully profiled through poly(lactic acid)-based polymeric materials as thick as 1000 nm (1 µm) and higher (data not shown). Similar results have been obtained from other biodegradable polyester-type structures such as PGA, PLGA, and polycaprolactone.35 Since the ability to depth profile in polymeric films has typically been limited to less than 200 nm in most cases, we can see that these particular materials are much more amenable to in-depth analysis with cluster SIMS.33,34 Table 1 lists the film thicknesses and average sputter rates for the materials analyzed in this work. The sputter rates were determined by measuring the film thicknesses using profilometry and dividing this thickness by the amount of time required to reach the interface (point at which Si intensity is 50% of its maximum value). The sputter rates of the blend films and PLLA film alone varied between 55 and 65 nm3/incident SF5+ or 0.70.8 nm/s (1000 µm × 1000 µm raster at 2-nA current). These values are extremely high with respect to most other polymeric materials and may be the primary reason these materials are more amenable to depth profiling.33,34 It is expected that materials with high sputter rates, in which the beam-induced damage is removed as fast as it is being created, will be more successful in depth profiling experiments. It is the buildup of beam-induced damage (molecular bond breaking) in these samples that limits the ability to obtain in-depth information. It is suspected that the biodegradable polyester structure is susceptible to main chain scission and thus has much faster rates of sputtering as compared to other polymeric materials.34,35 Also note that, in Table 1, there did not appear to be any significant changes in sputter rates with changing compositions. This is particularly interesting because the sputter rate of the P104, though only an approximation (film thickness measurements were difficult due to film roughness), was much lower. This means that, when in a PLLA matrix, the P104 sputters much more efficiently. It is assumed that there will be a point where the bulk concentration of P104 starts to affect the overall sputter rate of the blend material, although this point has not been reached in the current work. These results are consistent with what has been observed in earlier work describing depth profiling in acetaminophen-doped poly(lactic acid) films.35 In that study, attempts to obtain depth profiles of pure acetaminophen films were unsuccessful because the sputter rates were low and there was extensive damage to the sample. However, when the acetaminophen was incorporated into a poly(lactic acid) matrix, the molecular ion signal from the acetaminophen was successfully monitored as a function of increasing sampling depth with minimal degradation in signal. When taking a closer look at the interfacial (air/polymer) intensity variations in the profiles in Figure 2, we can see that Analytical Chemistry, Vol. 77, No. 11, June 1, 2005

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Figure 2. Secondary ion intensities (log scale) as a function of increasing SF5+ primary ion dose for PLLA films containing (a) 25% (w/w) Pluronic P104, (b) 10% (w/w) Pluronic P104, (c) 5% (w/w) Pluronic P104, (d) 25% (w/w) Pluronic P104 normalized to total ion intensity, (e) 10% (w/w) Pluronic P104 normalized to total ion intensity, and (f) 5% (w/w) Pluronic P104 normalized to total ion intensity. Where (2) represents the secondary ion intensity for m/z ) 128 (PLLA), (b) represents the secondary ion intensity of m/z ) 59 (P104), and (9) represents the secondary ion intensity of m/z ) 28 (Si).

Table 1. Film Thickness and Sputter Rates of PLLA/ P104 films % P104

film thickness (nm)

sputter rates (nm/s)a

sputter rates (nm3/incident SF5+)

0 1 2 4 5 10 25 100

705.5 ( 1.8 736.7 ( 10.0 769.7 ( 5.7 648.3 ( 24.0 726.5 ( 21.6 893.9 ( 16.7 619.7 ( 24.1 365.4 ( 29.1

0.73 ( 0.05 0.77 ( 0.01 0.73 ( 0.02 0.75 ( 0.07 0.68 ( 0.06 0.79 ( 0.02 0.75 ( 0.06 0.13 ( 0.02

58.6 ( 4.2 61.9 ( 0.7 58.8 ( 1.2 59.9 ( 5.9 54.5 ( 5.9 63.6 ( 1.6 60.2 ( 5.0 10.4 ( 1.2

a

2 nA continuous SF5+ current using 1000 µm × 1000 µm raster.

there is an increased P104 signal intensity at the surface of the film with a corresponding decreased PLLA signal intensity, followed immediately by a diminished P104 signal with corresponding PLLA signal enhancement in the subsurface region. This 3574 Analytical Chemistry, Vol. 77, No. 11, June 1, 2005

effect is more clearly demonstrated when the ratio of the P104 analyte signal (m/z ) 59) to that of the signal from the PLLA matrix (m/z ) 128) as a function of increasing SF5+ dose is monitored. These ratios were plotted up to the interfacial region (point where Si reaches 50% of its maximum intensity) for all samples. Figure 3 shows the resultant ratio profiles for samples containing 25%, 10%, 5%, and 0% (w/w) P104. As can be seen in all of the profiles except for the control containing 0% P104 (Figure 3d), there tends to be four separate regions of interest in all profiles examined. These regions are more clearly observable in the more concentrated samples (e.g., 25% and 10% samples). However, the effects were prevalent in all samples analyzed. Region 1 reflects a surface enriched P104 region, consistent with what has been observed in previous XPS and conventional TOFSIMS surface studies.1,20 Region 1 is immediately followed by region 2, which shows a region of depleted P104 concentration. Models describing the surfaces of polymer blends where one

Figure 3. Intensity ratios of m/z ) 59 (P104) to m/z ) 128 (PLLA) plotted as a function of increasing SF5+ primary ion dose for a PLLA films containing (a) 25% (w/w) Pluronic P104, (b) 10% (w/w) Pluronic P104, (c) 5% (w/w) Pluronic P104, and (d) 0% (w/w) Pluronic P104. Each of the profiles have numbers associated with different regions in the profile: 1, surface enriched P104 region; 2, P104 depletion zone; 3, bulk composition region; and 4, interfacial region.

component preferentially migrates to the surface predict such a depletion zone for reasons of mass balance. This region has also been found to exist in angle-dependent XPS models described in previous work.36-39 However, this is the first time we have been able to measure such a depletion zone directly using TOF-SIMS depth profiling. This region is then followed by region 3, which is the constant bulk composition region. It is expected that the concentration of P104 in this region will be consistent with the known bulk concentration. Finally, region 4, is the interfacial region, which appears to have a similar, but diminished effect as the surface region. Figure 3d represents the intensity ratio (m/z ) 59/128) profile of the PLLA alone and is placed here as a negative control. As expected, the profile has an entirely different shape and has an average bulk intensity ratio of ∼0.7. This value is attributed to background signal located at mass 59. Any changes in the intensity ratio as a function of increasing dose in the control sample are associated with charging or matrix effects due to sputtering. The primary reason for the diminished ratio at the surface in this control sample is associated with m/z ) 128, which typically has a much higher intensity in the surface region, and then rapidly decays with sputtering, at least within the first 1.0 × 1013 ions/ cm2 SF5+ (often referred to as the “static limit”: information obtained below this limit is associated with the surface of the material, while information obtained above this value is associated with the subsurface or bulk layers). This effect will be discussed in greater detail later in the next section, as it will play an important role particularly in the determination of concentrations in the

surface region. However, for now it can be clearly seen that the PLLA film itself has a completely different behavior under SF5+ bombardment, further indicating that the intensity variations observed in the blend films are a result of changing P104 content. Calibration and Quantification of Depth Profiles. The intensity ratio profiles shown in Figure 3 can be converted to composition depth profiles through a calibration curve, where average intensity ratios of m/z ) 59/128 are plotted as a function of changing known sample compositions. In this particular series of samples, there were two separate linear regions in the calibration, describing the low (0%-4%) and high (>5%) concentration samples. The equations describing these regions were y ) 0.162x + 0.678 (R ) 0.99209) and y ) 0.556x - 0.851 (R ) 0.99994) for the low- and high-concentration regions, respectively. For more information regarding the calibration process, see the Supporting Information (Figure 1s). The resulting compositional depth profiles obtained are shown in Figure 4. One can see that the measured bulk compositions in the profile are consistent with the compositions of the prepared samples. One can also see that the P104 surface compositions increase with increasing bulk content. Thus, we know that we can use this methodology to obtain information about relative sample compositions as a function of depth. One can also potentially obtain information about the relative thickness between the samples as long as the thickness is greater than the depth resolution, and the changing sputter yields as a function of primary ion dose are accounted for. The surface overlayer thickness of P104 as predicted by XPS is ∼3.5 nm.36 The limitation in sampling Analytical Chemistry, Vol. 77, No. 11, June 1, 2005

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Figure 4. Composition depth profiles as determined using the calibrations described in Figure 4 for samples containing (a) 25% (w/ w) Pluronic P104 in PLLA, (b) 10% (w/w) Pluronic P104 in PLLA, and (c) 5% (w/w) Pluronic P104 in PLLA.

depth with XPS is typically 10 nm (up to 20 nm with higher energy X-ray sources), so for thicknesses greater than this, cluster SIMS can potentially be used. In this particular case, the P104 overlayer thicknesses are most likely too thin to obtain accurate thicknesses measurements using SIMS. However, we can make an attempt to approximate the thickness by taking the derivative of the SIMS depth profiles shown in Figure 4 (plotted on a depth scale), where the first inflection point was approximated to be the thickness of the P104 layer in the sample. The depth scale was determined using equations described in earlier work.33 For the 5%, 10%, and 25% samples, the approximate thicknesses as determined by the SIMS composition depth profiles were 3.6, 4.0, and 4.8 nm respectively. These values are consistent with the XPS data. 3576

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Table 2 lists the sample compositions determined from different regions in the SIMS composition depth profiles as compared to the known bulk compositions and XPS data.20 Note that the bulk compositions as determined from the composition depth profiles are consistent with the actual sample compositions. Note also that the average composition measured over the whole depth profile is also consistent with the actual compositions. Hence, this quantification procedure has been successful in the determination of bulk compositions, and if an unknown sample of P104 in PLLA were analyzed, it is expected that we could determine the composition of the sample using this approach (assuming the matrix is similar). The surface compositions listed in the table were not determined in the same manner as the surface compositions of P104 as extracted from the SIMS depth profiles (2.54 ( 0.39%, 6.67 ( 0.51%, 9.45 ( 0.42%, 17.27 ( 3.41%, 26.06 ( 5.77%, and 67.42 ( 20.45% for 0%, 1%, 2%, 4%, 5%, 10%, and 25% sample compositions respectively), but by correcting surface compositions for changing secondary ion yields in the static region. Figure 5 depicts the surface composition as a function of changing bulk compositions as determined by both XPS and SIMS so that we can make a direct comparison between the two methods. As can be seen initially, the SIMS data (b) are linear while the XPS data (9) show exponential decay characteristics. Both techniques show a greater P104 composition than the unit line (2), which describes the case where there is no preferential segregation (that is to say, the composition at the surface is equal to that in the bulk). Attempts were made to further understand the discrepancies between the XPS data and the SIMS data in the surface region resulting in the final curve in Figure 5, plotting the corrected SIMS surface concentrations (1), which were more consistent with the XPS data (next section). Corrections in the Surface Region. Figure 6 shows the depth profiles (in particular the m/z ) 128 and m/z ) 59 intensities) of the PLLA and Pluronic surfactant films by themselves. As can be seen in the case of the PLLA film, within the first 15 s of the depth profile (∼1.84 × 1013 SF5+ ions/cm2) there is a dramatic drop in signal (this is much more clearly observed on a linear scale). This effect, though common, was not observed in the Pluronic depth profile shown in Figure 6b. In fact there is typically a small increase in signal, but overall a very small difference in comparison to the signal drop that occurs in the PLLA sample. The effects shown here are consistently seen in all films of PLLA and P104, even in different molecular weights and crystallinities. On average, the intensity ratio of the first point in the m/z ) 128 profile to the average bulk intensity of m/z ) 128 is 0.246 ( 0.022 for the PLLA depth profile alone. In other words, the signal intensity of m/z ) 128 at the surface is 5 times higher than that observed in the bulk for the PLLA sample after sputtering for 15 s. For the Pluronic depth profile, this ratio of m/z ) 59 at the surface to the bulk intensity is 1.023 ( 0.004. It is obvious that this type of signal degradation in the static region will affect the accuracy of the quantitative information obtained in the surface region. However, also note that the secondary ion signal remains stable during the remainder of the profile, indicating that quantification in the bulk region should be fairly accurate. By examining the depth profiles at varying compositions of P104, it is seen that this m/z ) 128 signal variation effect is much more prominent in the lower concentration samples,

Table 2. Compositional Depth Profile Information As Compared to Known Bulk Compositions and XPS Dataa actual sample composition

XPS (15o take-off angle, 25 Å)20

bulk P104 comp (wt %)

surface P104 comp (wt %)

corrected surface P104 comp (wt %)

interfacial concn of P104 (wt %)

average P104 concn (wt %)

bulk P104 comp (wt %)

location of minimum (nm)

1 2 4 5 10 25

7.5 27.5 41.0 47.5 56.0 66.0

23.11 ( 1.58 39.85 ( 2.07 50.90 ( 1.86 56.38 ( 3.37 63.40 ( 17.82 67.42 ( 20.45

3.71( 0.39 6.67 ( 0.51 10.01 ( 0.33 11.88 ( 3.19 14.40 ( 1.02 30.07 ( 2.73

1.37 ( 0.02 2.15 ( 0.02 4.16 ( 0.27 5.57 ( 0.46 9.66 ( 0.27 24.06 ( 2.20

1.37 ( 0.01 2.09 ( 0.05 3.96 ( 0.10 4.88 ( 0.047 9.51 ( 0.35 30.34 ( 3.18

15.8 ( 3.1 16.5 ( 1.8 19.7 ( 4.9 24.2 ( 4.9 32.0 ( 4.7 48.8 ( 6.3

a

information extracted From SIMS depth profiles

All average values and standard deviations based on three measurements.

Figure 5. Surface compositions of various samples as determined by (9) XPS, second-order exponential fit (R2 ) 0.998); (b) TOF-SIMS uncorrected, linear fit (slope 2.66, y-intercept ) 0.72, R2 ) 0.994), and (1) TOF-SIMS after corrections, second-order exponential fit (R2 ) 0.999). (2) Unit line: linear fit (slope 1, y-intercept ) 0, R2 ) 1).

which have more PLLA exposed at the surface as a result of the decreased P104 coverage. Though it is obvious in the lowconcentration depth profiles (e.g., 1%-4%, where a decrease in the intensity of m/z ) 128 at the surface is observed, similar to what is observed in Figure 6), this effect can still be seen in the 5% and 10% composition depth profiles, where there is an initial m/z ) 128 intensity spike. To determine how this initial signal drop affects the surface compositions as determined by SIMS, attempts were made to correct for this by multiplying the surface intensity ratio by 0.246 (see above) to normalize the surface intensity of m/z ) 128 to the bulk intensity. This was only done at concentrations lower than 5% as this is where the most significant m/z ) 128 signal decay was observed. This correction was not applied in an effort to obtain accurate SIMS quantification in the surface region, but rather as a means to determine what would happen to the data trend if this effect were not there. At higher concentrations, this effect is greatly diminished due to increased surface coverage of P104, which has a very minor surface intensity variation resulting from SF5+ damage. Hence, the more concentrated samples (5%, 10%, and 25% P104) were treated differently. In the 5% and 10% P104 samples, the first point was estimated by extrapolation. For

Figure 6. Secondary ion intensities (log scale) as a function of increasing SF5+ primary ion dose for (a) pristine PLLA film and (b) Pluronic P104 film, where (9) represents the secondary ion intensity for m/z ) 128 (PLLA) and (b) represents the secondary ion intensity of m/z ) 59 (P104).

example, in Figure 2b, the “corrected” first point can be estimated by drawing a line from the next few points, which are following the expected trend. In doing so, one can obtain an idea of where the point would have been located had this PLLA signal drop affect not been present. The actual values shown in Table 2 for the 5% and 10% samples represent an average between the two methodologies (e.g., extrapolation and normalization of first point). The 25% P104 sample surface intensity ratio was left as it was originally Analytical Chemistry, Vol. 77, No. 11, June 1, 2005

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calculated. It is assumed here that the effect is negligible as the actual compositions are consistent with the XPS compositions. The results of the corrected intensities are plotted in Figure 5. The compositions determined by TOF-SIMS after data correction are consistently higher than the surface compositions as determined by XPS. This could be a result of TOF-SIMS being a more surface-sensitive technique than XPS. Also note that the resulting corrected surface concentrations have a shape that is similar to that observed in the XPS calculations, indicating that the XPS compositional information obtained is most likely accurate. Thus, quantification in the surface and bulk regions should be treated differently when utilizing SIMS depth profiling. CONCLUSIONS Time-of-flight secondary ion mass spectrometry employing an SF5+ polyatomic primary ion beam source was utilized for the first time to obtain in-depth information from a polymeric blend system where one component was preferentially segregating to the surface and dominating the surface properties. In these profiles, the ratio of m/z ) 59, a fragment ion associated with the Pluronic additive P104, to m/z ) 128, a fragment ion associated with the PLLA matrix, was monitored as a function of increasing SF5+ primary ion dose. Each SIMS depth profile indicated a surface enriched P104 region, consistent with what was observed with XPS. This surface enriched P104 region was then directly followed by a P104 depleted region, and then finally a constant composition region associated with the bulk. The shapes of these depth profiles are consistent with theoretical models of the surface describing preferential segregation in polymeric blends and copolymer systems. This is the first time it has been possible to directly verify such models.

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Quantification in these samples was attempted by utilizing calibration curves for samples of varying concentrations. The resulting composition depth profiles obtained from these calibrations were accurate in the bulk and subsurface regions, and thus, it is believed that SIMS can potentially be used to determine unknown sample compositions, both average and as a function of depth. The concentrations at the surface as determined by SIMS increased linearly with increasing bulk concentration, a trend very different from what was observed in the XPS data. When corrections were made in the surface region accounting for changing secondary ion yields, the corrected surface concentrations followed an exponential trend that was consistent with the data determined by XPS. This means that, for purposes of SIMS quantification, the surface and bulk regions need to be treated differently. Most importantly, this work demonstrates the utility of cluster SIMS for determination of compositional gradients in selected polymeric blends. In-depth analysis of surface segregated materials in polymeric blends is important for many applications including nonfouling, adhesive, pharmaceutical, and biomaterial industries. The particular blend system described in this work can be utilized for protein drug delivery devices. It is hoped that this technology will help with future product development and quality control for polymeric blend materials. SUPPORTING INFORMATION AVAILABLE Additional information as noted in text. This material is available free of charge via the Internet at http://pubs.acs.org. Received for review November 22, 2004. AC048274I