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1 Powder Technology 212 (2011) Contents lists available at ScienceDirect Powder Technology journal homepage: A material sparing method for quantitatively measuring tablet sticking Todd S. McDermott a,, Jochen Farrenkopf b, Anthony Hlinak a,1, Joseph P. Neilly a, Dorothea Sauer a,2 a Abbott Laboratories, Global Pharmaceutical Sciences, 200 Abbott Park Road, Abbott Park, Illinois 60064, USA b Abbott GmbH & Co. KG, Global Pharmaceutical Sciences, Knollstrasse 50, Ludwigshafen, Germany article info abstract Article history: Received 13 October 2010 Received in revised form 5 April 2011 Accepted 26 May 2011 Available online 1 June 2011 Keywords: Sticking Picking Punch adhesion Excipients Formulation SEM/EDS imaging methods The aim of this study was to develop a material-sparing method to quantitatively measure sticking during tablet manufacturing and to allow direct comparison of blends in terms of sticking. A protocol has been developed for quantitation of API layering on punch faces using HPLC analysis. Tabletting runs were carried out such that different numbers of tablets were produced by each punch set. The punch faces were quantitatively extracted and the concentration of API in the extraction solutions was determined by HPLC analysis. The amount of API on the punch faces increases linearly with the number of tablets produced (cycles). This relationship has been demonstrated on both a single station press (Fette) and on a rotary press (Riva, Piccola) and for a number of different API blends. The method was used to study the impact of MCC grade, lubricant concentration and solid fraction on sticking behavior. With all other variables constant, blends with Vivapur 102 as filler showed more layering than blends with Avicel PH 102 as filler. Increased solid fraction and increased MgSt concentration led to decreased API layering. The elemental make-up of the material adhered to the punch face was characterized by SEM/EDS analysis and was compared to the elemental make-up of the blend. The material adhered to the punch surface was enriched in API and silicon dioxide (SiO 2 ) relative to the blend Elsevier B.V. All rights reserved. 1. Introduction A major concern during the development of a tablet formulation is sticking of material to tooling surfaces. In some cases this leads to layering of material to the punch surfaces. In more extreme cases sticking can lead to tablet defects due to picking of material from tablet surfaces. Unfortunately, the tendency of a formulation to result in sticking and picking is often not identified until late in the development process when mitigation options are limited [1]. Formulation experience shows that in some cases there is a buildup of material on punch surfaces as a tabletting run continues. However, there is very little in the literature about identification or quantitation of material on the punches, despite the importance for screening and formulation optimization purposes [2 4]. The hypothesis being investigated in this study is that the material that builds up on punch faces during tabletting runs is enriched in API and that quantitation of the amount of API present on the punch faces is possible. A reliable method to quantitatively measure the amount of API on punch faces would allow testing of the axiom that material (API) continues to build up on punches during a run. Demonstration of a systematic increase in punch layering with the number of tablets Corresponding author. Tel.: ; fax: address: todd.mcdermott@abbott.com (T.S. McDermott). 1 Present address: AJ Ryan Engineering, 9815 Falcon Drive, Richmond, IL 60071, USA. 2 Present address: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. produced could allow measurement of a blend's sticking tendency. Additionally, optimization of a formulation with respect to sticking could be carried out with minimal API. There are two distinct phases of the sticking process. During the initial phase, part of the blend begins to adhere to the punch face surfaces. This phase is dominated by the tug of war between adhesion, the propensity of particles to adhere to other surfaces, and cohesion, the propensity of like particles to stick together [5]. Methods that have been used to investigate these forces include atomic force microscopy (AFM) [1] and direct separation [6]. The second phase of the sticking process is the increase in layering as a tabletting run continues. The newly compressed tablet is no longer interacting with the punch surface at all, but is contacting a layer of material that is already adhered to the punch surface. The adhesion force is now different and not easily measured. Investigation of adhesion and cohesion can give a general idea of the material properties at a particle level. However, on a more practical level sticking is related to the behavior of the blend with the particular tabletting equipment being used. There have been several methods published that try to quantitatively measure the sticking behavior of blends during compression. These include measurement of slipping force between upper punches and tablets after compression [7], measurement of sweep-off force [8] and measurement of take-off force using an instrumented upper punch [5]. These methods provide a quantitative approach to the evaluation of sticking, but suffer from measurement under unrealistic conditions (slipping force), low signal to noise (sweep-off force) or the need for elaborate equipment (instrumented punch) /$ see front matter 2011 Elsevier B.V. All rights reserved. doi: /j.powtec

2 T.S. McDermott et al. / Powder Technology 212 (2011) The study presented here offers an alternative approach. Tabletting was carried out in the normal manner using typical equipment. The sticking tendencies of the blends were determined by evaluation of the tablet tooling using quantitative analytical techniques. The amount of API present on the punches was measured by carefully extracting the adhered material and evaluating by HPLC. By carefully controlling the experimental variables, direct comparison of the sticking tendencies of different blends is possible. The material present on the punch faces was characterized using scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS). Fig. 1. ABT-089 and ABT-279 are model compounds used for this study. 2. Materials and methods 2.1. Materials The materials utilized for this study are listed in Table 1. The active pharmaceutical ingredients (APIs) used were ABT-089 and ABT-279 (Fig. 1). In early development, each of these materials exhibited sticking during compression, making them ideal model compounds for an in-depth investigation of sticking. Both APIs are water soluble (N20 mg/ml) allowing water to be used for all extraction studies Methods Blending A series of blends with varying amounts of magnesium stearate (MgSt) and different drug loads were prepared as described in Table 1. Two different blending protocols were utilized for this work. Blending Protocol A: The Aerosil 200 (SiO 2 ) and croscarmellose sodium (CC) were weighed and passed through a 0.8 mm screen followed by a small portion of the Avicel PH102 (Avicel) or Vivapur 102 (Vivapur). The API was sandwiched between layers Avicel or Vivapur in a bin. The sieved mixture was added on top and the contents of the bin were blended for 5 min with a Turbula blender (Model T 10 B, Willy A. Bachofen AG Maschinenfabrik, Muttenz, Switzerland). MgSt, which had been weighed and passed through a 0.8 mm screen, was added and the mixture was blended for 2.5 min with a Turbula blender. Blending Protocol B: The SiO 2 and CC were weighed and passed through a 30-mesh screen followed by a small portion of the Avicel. The API was sandwiched between layers of Avicel in a 3.8-L V-blender shell and the sieved mixture was added on top. The material was blended at 26 rpm for 10 min with a V-blender (Blend Master, Patterson-Kelley, East Stroudsburg, PA). MgSt, which had been weighed and passed through a 30-mesh screen, was added and the mixture was blended at 26 rpm for 5 min with a V-blender. True Table 1 Materials and blending conditions utilized for these studies. Name (abbreviation) Formulation I II III IV V VI VII (%) a (%) a (%) b (%) b (%) b (%) b (%) b ABT-089 tartaric acid salt (ABT-089) ABT-279 malic acid salt (ABT-279) Avicel PH 102 microcrystalline cellulose (Avicel) Vivapur 102 microcrystalline cellulose (Vivapur) Croscarmellose Sodium (CC) Aerosil 200 colloidal silicon dioxide (SiO 2 ) Magnesium stearate (MgSt) a Blending protocol A: 10-L bin blended with a Turbula blender for 5 min without MgSt and 2.5 min with MgSt. b Blending protocol B: 3.8-L V-container blended at 26 rpm for 10 min without MgSt and at 26 rpm for 5 min with MgSt. densities of all blends were determined using helium pycnometry (AccuPyc 1330, Micromeritics, Norcross, GA) Compression Tablets were produced using either a single punch press (Fette E1, Fette GmbH, Schwarzenbek, Germany) equipped with Ritter tooling (6 mm length, 8.78 mm radius with an upper bisect, Ritter Tablettierwerkzeuge, Hamburg, Germany) or a rotary tablet press (Piccola B, Riva, Ciudadela, Argentina) equipped with Elizabeth-Carbide tooling (6.35 mm length, 6.43 mm radius with an upper bisect, Elizabeth Carbide, Lexington, NC). Tablets were compressed at a target weight of 100 mg and to a specific solid fraction. Tablet weight, thickness and hardness were determined within 24 h of the tabletting run using an automated tablet tester (ElizaTest 3+, Elizabeth-Hata, North Huntingdon, PA). The tooling dimensions and the average thickness of 10 tablets were used to calculate tablet volume. Solid fraction was calculated using the blend true density, the calculated volume, and the average tablet weight. The average tablet thickness generally decreased during the runs due to build up of material on the punch faces. Although this caused the calculated solid fraction to increase through the runs, the weights were held constant. The reported solid fractions reflect the solid fractions at the start of the run Quantitation of API layering on a single-punch press A single-punch tablet press was equipped with a punch set and the tablet weight and thickness were adjusted to produce tablets of the desired solid fraction. The press was not equipped to allow measurement of compression force. The punches were removed and washed with water, rinsed with EtOH, dried and reinstalled. A tabletting run was carried out such that 250 tablets were produced by the punch set (5 min 13 s at 48 tablets/min). The tooling was removed, being careful not to disturb the punch faces, and the API on the punch faces was extracted as follows. The loose powder was removed from the body of the punches with a vacuum cleaner and a damp cloth, being careful not to disturb the punch faces. The upper and lower punch tips were immersed in a small amount of water and a wet cotton swab was used to loosen material from the tips. The punch tips and cotton swab were rinsed three times each with clean water. All of the water was collected and transferred to a 10-mL volumetric flask and diluted to the mark with water. The concentration of API in the extraction water was determined by comparison to a standard HPLC solution. HPLC data were generated on a Waters Alliance 2695 HPLC. HPLC Conditions: Column: YMC-Pack- Pro C4, 250 mm 4.6 mm, 5 μm, 35 C, 1 ml/min, 10 μl injection, λ 284 nm; Mobile phase A: 20 mm KH 2 PO 4, 20 mm heptane-1-sulfonic acid sodium salt in water adjusted to ph 2.5 with H 3 PO 4 ; Mobile phase B: MeOH; Gradient: 0 min 40% B, 10 min 50% B, 11 min 40% B; Retention time (min): ABT-089 (6.2). After extraction, the punches were cleaned with water and ethanol, dried and reinstalled. A second run was carried out such that 500 tablets were produced by the punch set (10 min 25 s at 48 tablets/min). The punches were removed and extracted as described above. This procedure was repeated with varying numbers of tablets produced (cycles). In order to avoid changes in dwell time, all

3 242 T.S. McDermott et al. / Powder Technology 212 (2011) tabletting runs were carried out with the same set of tooling and at the same production speed Quantitation of API layering on a rotary tablet press A rotary tablet press was equipped with 3, 4 or 5 punch sets in consecutive positions and the tablet weight and thickness were adjusted to produce tablets of the desired solid fraction. The compression force necessary to achieve the desired solid fraction ranged from 3 to 6 kn, depending on the solid fraction. In order to avoid changes in dwell time, all tabletting runs were carried out with the same sets of tooling and at the same production speed. The tabletting run was started and upper punches were removed at predetermined time points. Removal of the upper punch limits the compression exposure of that punch set. In this way a single tabletting run results in a series of punch sets that have produced different numbers of tablets (cycles). A production speed of 50 rpm was used and tablets were collected every five minutes during the run. After the run, the lower punches were removed. Each of the punches was extracted as described above. API layering for upper and lower punches was measured separately. The HPLC data were generated on an Agilent 1100 series HPLC (Agilent Technologies, Inc., Santa Clara, CA). HPLC Conditions (ABT-089): Column: YMC-Pack-Pro C8, 150 mm 4.6 mm, 3 μm, 25 C, 1 ml/min, 10 μl injection, λ 214 nm; Mobile phase A: 10 mm PO 4, in 90:5:5 H 2 O/CH 3 CN/MeOH at ph 6.5; Mobile phase B: 30:50:20 Mobile phase A/CH 3 CN/MeOH; Gradient: 0 min 0% B, 7.5 min 50% B; Retention time (min): ABT-089 (4.7). HPLC Conditions (ABT-279): Column: YMC-Pack-Pro C8, 150 mm 4.6 mm, 3 μm, 25 C, 1 ml/min, 10 μl injection, λ 210 nm; Mobile phase A: 10 mm PO 4 -, in 90:5:5 H 2 O/CH 3 CN/MeOH at ph 6.5; Mobile phase B: 30:50:20 Mobile phase A/CH 3 CN/MeOH; Gradient: 0 min 20% B, 7.5 min 65% B; Retention time (min): ABT-279 (4.2) Characterization of material on punch faces The material adhered to the punch faces was visualized by scanning electron microscopy (SEM) and characterized by energy dispersive X-ray spectroscopy (EDS) using either a FEI XL30 environmental scanning electron microscope with an Edax Genesis 4000 energy dispersive system with light element X-ray detector or a FEI Quanta 400 field emission scanning electron microscope with an Edax Genesis 4000 energy dispersive system with light element X-ray detector (FEI Company, Hillsboro, OR; EDAX Inc., Mahwah, NJ). Energy dispersive X-ray spectroscopy micro-analysis is performed by measuring the energy and intensity distribution of X-ray signals generated by a focused electron beam on the sample. With the attachment of the energy dispersive detector, the elemental composition of materials can be obtained. X-ray energy and intensity are correlated with electron beam position on the sample in a technique known as X-ray mapping. Nitrogen, magnesium, sodium and silicon are unique to API, MgSt, CC and SiO 2, respectively. EDS was used to localize components on hand-compressed blend samples and on punch faces after compression. These data are presented as images with the component of interest highlighted. Fig. 2. API layering versus number of tablets produced (cycles) for Formulation I (20% ABT-089) compressed to 76 and 90% solid fraction on a single-punch tablet press For regression coefficient determination a 0 cycles, 0 mg API point is included for experiments run on the single-punch press. Next, the technique was used to investigate the effect of formulation and processing parameters on the extent of API layering Impact of solid fraction It is well known that increased compaction force has a positive impact on sticking [9]. To quantify the effect of compression force on API layering, tabletting runs at different solid fractions were compared. Fig. 2 shows comparison of the initial tabletting run at 76% solid fraction with a run carried out at 90% solid fraction. For the 90% solid fraction experiment, runs of 250, 600 and 5000 cycles were carried out. Again, there is a linear relationship between the number of cycles and the amount of API layered on the punches (r 2 =0.9999) Impact of excipients MCC Formulation II was prepared with Vivapur 102 as the filler (Table 1) and tabletting runs were carried out at 76 and 90% solid fraction. Each run showed a linear increase in layering with the number of cycles with regression coefficients of and , respectively. Again, increased solid fraction resulted in lower API layering (shallower slope). Additionally, at the same solid fraction the 3. Results 3.1. Quantitation of API layering on a single-punch press The initial tabletting experiment was carried out by compressing Formulation I to 76% solid fraction using a single-punch press. Tabletting runs of 250, 500, 1000, 2000 and 5000 tablets were carried out. After each run, the upper and lower punches were extracted together as described above. A plot of the number of tablets produced by each punch set (cycles) versus the amount of API present on the punch faces, as determined by HPLC analysis, is shown in Fig. 2. There is a linear relationship between the number of cycles and the amount of API layered on the punches, with a regression coefficient (r 2 )of Fig. 3. Comparison of API layering for Formulation I (20% ABT-089/Avicel) and Formulation II (20% ABT-089/Vivapur) compressed to 76 and 90% solid fraction on a single-punch tablet press.

4 T.S. McDermott et al. / Powder Technology 212 (2011) Impact of solid fraction The impact of solid fraction on API layering was shown for ABT-089 blends compressed on a single-station tablet press (Figs. 2 and 3). A series of runs was carried out with Formulations III, IV and V to determine the impact of solid fraction on API layering for the rotary tablet press. The layering lines for each of these studies, generated by extraction of lower punches, are shown in Fig. 6. Fig. 4. Upper and lower punch layering results for Formulation III (20% ABT-089) compressed to 82% solid fraction using a rotary tablet press. Avicel blends showed decreased layering relative to the Vivapur blends (Fig. 3) Quantitation of API layering on a rotary tablet press Formulation III was prepared (Table 1) and compressed to 82% solid fraction on a rotary tablet press. Upper punches were removed at predetermined time points resulting in production of a different number of tablets for each punch set. For this experiment, a cycle run was carried out with five punches and upper punches were removed at 250, 500 and 1000 cycles, leaving two punch sets at 2500 cycles. The API layering data for the upper and lower punches, which were extracted separately, are shown in Fig Impact of MgSt concentration A series of studies was carried out to quantify the impact of MgSt concentration on API layering. Formulations III, IV and V, with MgSt concentrations of 0.75%, 1.00% and 1.25%, respectively, were compressed to 82% solid fraction. For Formulation III, a 7000-cycle run was carried out with five punch sets and upper punches were removed at 500, 1000, 3000 and 5000 cycles. For Formulations IV and V, cycle runs were carried out with four punch sets and upper punches were removed at 500, 1000 and 2000 cycles. The upper and lower punch faces were extracted as described earlier. The results for the lower punches are shown in Fig. 5. Fig. 5. API layering on lower punches after compression of Formulations III (0.75% MgSt), IV (1.00% MgSt) and V (1.25% MgSt) to 82% solid fraction on a rotary tablet press. Fig. 6. A series of runswerecarriedout on a rotary tablet press to examinetheeffectofsolid fraction at different MgSt concentrations. The data presented are for extraction of lower punches. (a) Formulation III (0.75% MgSt) was compressed to 82% and 92% solid fraction. (b) Formulation IV (1.00% MgSt) was compressed at 72% and 82% solid fraction. (c) Formulation V (1.25% MgSt) was compressed at 71, 82 and 92% solid fraction.

5 244 T.S. McDermott et al. / Powder Technology 212 (2011) Characterization of adhered material SEM/EDS analysis was used to localize specific elements in order to identify the material adhered to the punch face and to compare to the corresponding blend. A small portion of Formulation III was handcompressed to produce a flat surface for imaging. Formulation III was compressed to 82% solid fraction for 3000 cycles using a rotary tablet press and a lower punch face was analyzed by SEM/EDS. The corresponding SEM images and X-ray maps are shown in Figs. 7 (blend) and 8 (punch) Extension of the method In an effort to determine the generality of the API quantitation method, an investigation of the layering behavior of another API, ABT- 279, was carried out. Blends of ABT-279 at 5% drug load (Formulation VI) and 10% drug load (Formulation VII) were prepared using blending protocol B (Table 1). Formulation VI was compressed to 82% solid fraction for 5000 cycles with upper punches removed at 500, 1000, 2000 and 3500 cycles and Formulation VII was compressed to 82% solid fraction for 1000 cycles with punches removed at 250 and 500 cycles. The layering lines for these runs are shown in Fig Characterization of adhered material ABT-279 As with ABT-089, SEM/EDS was used to characterize the elemental make up of the blend and the material adhered to the punch face after compression of an ABT-279 blend. Fig. 10 shows the SEM image and elemental maps for a hand-compressed compact of Formulation VII (10% ABT-279). Formulation VII was compressed to 85% solid fraction for 1250 cycles on a rotary press. One of the lower punches from the run was analyzed by SEM/EDS and the images are shown in Fig. 11. Fig. 7. Elemental distribution of a hand-compressed compact of Formulation III (20% ABT-089).

6 T.S. McDermott et al. / Powder Technology 212 (2011) Fig. 8. Elemental distribution of the lower punch face after compression of Formulation III (20% ABT-089) to 82% solid fraction for 3000 cycles Reproducibility of the method In an effort to limit the amount of material needed, a 1250-cycle run was carried out using four punch sets with upper punches removed at 500, 750 and 1000 cycles, resulting in a total of 3500 tablets. The comparison of this run, which utilized Formulation III compressed to 82% solid fraction, to runs of 7000 and 2500 cycles carried out with the same formulation under the same conditions, is shown in Fig Discussion 4.1. Observation of layering behavior Fig. 9. Formulation VI (5% ABT-279) and Formulation VII (10% ABT-279) were compressed to 82% solid fraction using a rotary tablet press. The data shown are for lower punches. For both ABT-089 and ABT-279, there is a gradual build-up of material on the punch faces with some concentration in the center of the lower (smooth) punch and near the bisect of the upper punch.

7 246 T.S. McDermott et al. / Powder Technology 212 (2011) Fig. 10. Elemental distribution of a hand-compressed compact of Formulation VII (10% ABT-279). Fig. 13 shows typical layering behavior for ABT-089 from 0 to 1250 cycles. The material adhered to the punch faces is firmly attached. Any loose material present is removed with a vacuum cleaner prior to extraction of the adhered material. For the APIs studied, the linear relationship between the number of cycles and the amount of API adhered to the punch faces continues for a large number of compression cycles. For ABT-089, the linear relationship continues to 7000 cycles (r 2 =0.9978, see Fig. 5) and for ABT-279, the linear relationship continues for 5000 cycles (r 2 =0.9955, see Fig. 9). Tabletting runs to larger numbers of cycles were not performed. It is unclear if the linear relationship between cycles and API layering would continue indefinitely or if this phenomenon is generally applicable to other APIs [10] Quantitation of API layering on a single-punch press The initial API layering experiments were carried out using a single-punch tablet press and one set of punches. The goal was to limit the number of variables impacting API layering in order to determine the feasibility of quantitatively extracting material from the punch faces and the correlation between number of tablets produced and the amount of API layering. Use of a single punch set removes the issue of punch to punch variability. Formulation I, containing 20% ABT-089, was compressed to 76% solid fraction and the upper and lower punches were extracted together. The initial experiment verified that it is possible to quantify the API layered on the punch faces and that the amount of API increases linearly with the number of cycles. The sensitivity of the method to processing conditions was demonstrated by tabletting the same blend at 90% solid fraction. There is a clear difference in slopes of the layering lines for these data sets. A shallower slope indicates less layering. As has been reported in the literature, increased compression leads to a decrease in layering [9]. These experiments are summarized in Fig. 2. The sensitivity of the method to formulation changes was investigated. There are a wide range of microcrystalline cellulose (MCC) grades available. Two grades, Vivapur 102 and Avicel PH 102 were evaluated

8 T.S. McDermott et al. / Powder Technology 212 (2011) Fig. 11. Elemental distribution of the lower punch face after compression of Formulation VII (10% ABT-279) to 85% solid fraction for 1250 cycles. for their effect on sticking of ABT-089 formulations. These MCC grades were chosen because, although they have identical chemical makeup and similar particle size, their surface morphologies are different as a result of the processes used to produce them. Vivapur 102 has a rougher surface with more crevasses relative to the Avicel PH 102. Formulation II, containing Vivapur 102 as a filler, was compressed to 76 and 90% solid fraction and these runs were compared to the original Avicel PH 102 runs. At both solid fractions, the Vivapur blends showed increased API layering relative to the Avicel blends. This effect was more pronounced at lower solid fraction. The source of the impact of MCC on sticking is not clear, but these results suggest that the surface properties of the MCC are important. One of the advantages of the rougher surface of Vivapur is that small API particles are held more tightly. This could result in improved flow, but might also limit the interaction of the API with the MgSt lubricant, thus leading to increased API layering Quantitation of API layering on a rotary tablet press The initial results generated on the single-punch press validated the punch extraction procedure and verified that layering of API on the punch surfaces linearly increases with the number of cycles. However, the technique is very time consuming since each point of the layering graphs represents a complete tabletting run starting from 0 cycles. A rotary tablet press allows all of the points for a layering line to be produced by a single run. This is accomplished by starting with multiple punches and removing upper punches at predetermined time points during a run. Removal of upper punches during the run limits the compression exposure for that punch set. As a proof of concept experiment, Formulation III (20% ABT-089) was compressed to 82% solid fraction and punches were removed periodically through the run and upper and lower punches were extracted. The layering lines for upper and lower punches, which

9 248 T.S. McDermott et al. / Powder Technology 212 (2011) Fig. 12. Formulation III (20% ABT-089) compressed to 82% solid fraction on a rotary press with runs of 7000, 2500 and 1250 cycles. The data shown are for extraction of lower punches. For clarity, the x-axis is displayed to 3200 cycles, although all data points were used for determination of the linear regression. were extracted separately, are shown in Fig. 4. Upper and lower punches each show a linear increase in the amount of API layering with the number of cycles, with regression coefficients of and , respectively. For analysis of the data from the rotary press, a zero point was not included. The amount of material necessary for set up is variable and the punches cannot be cleaned after setting the solid fraction. Therefore, the y-intercept (the amount of API present at 0 cycles) is different for each run. It is the slope of the layering line, rather than the absolute value of the API layering, that is important. In this experiment, and as was observed for most subsequent runs, lower punches showed increased API and higher regression coefficients relative to upper punches. That upper and lower punches show different layering behavior is not surprising. The upper punch is detached from the newly formed tablet by withdrawal of the punch vertically, imparting a normal force. The tablet is swept off of the lower punch from the side, imparting a shear force. The anisotropy in the tablet, a result of the uni-axial compression event that formed the tablet, results in different cohesive strengths in the axial and radial directions [11]. For the remaining experiments, upper and lower punches were extracted and analyzed separately, but only the lower punch results are presented Impact of formulation and processing on layering MgSt is the most widely used lubricant and numerous studies have been published investigating its impact on sticking, manufacturability and tablet properties [12 14]. It is generally accepted that increasing the concentration of MgSt in a formulation leads to improvement in sticking, but quantitation of the impact under real world conditions has not been widely reported. Fig. 5 shows layering lines for the series of blends with different concentrations of MgSt. Consistent with literature reports, increased MgSt concentration leads to lower API layering on the punches (shallower slope). There are several interesting observations about the data presented in Fig. 5. First, there is a linear relationship between the number of cycles and the amount of API present on the punch faces for all of the blends, with regression coefficients ranging from to Second, Formulation III was compressed to 7000 cycles and demonstrates linearity over the whole range (r 2 =0.9978). In order to spare API, subsequent runs were limited to fewer cycles. Finally, Fig. 14 shows a plot of the slopes of Fig. 5 layering lines versus MgSt concentration at constant solid fraction. There is a decrease in the slope of the layering line with increasing MgSt concentration. One of the easiest processing variables to adjust during tablet development is compression force. Typically, the goal is to determine the compression force that leads to appropriate tablet hardness, disintegration and, perhaps, dissolution. However, compression force also has an impact on sticking. It is possible to improve sticking during a run simply by increasing the compression force temporarily [9].Itis shown in Fig. 6 that at a variety of MgSt concentrations, increased solid fraction (compression force) leads to lower API layering. Each of the seven layering lines in Fig. 6 shows a linear relationship between the number of cycles and the amount of API layering with r 2 values ranging from to The lowest regression coefficient is for the high MgSt/high solid fraction run, Fig. 6c. The amount of material present on the punch faces for this run was very small exacerbating the impact of the inherent variability in the extraction and HPLC methods. Fig. 15 shows a plot of the slopes of the layering lines from Fig. 6c versus solid fraction at constant MgSt concentration (1.25%). There is a decrease in the slope of the layering line with increasing solid fraction. The analysis presented in Figs. 14 and 15 is based on limited data points but each shows a clear trend of decreasing layering with either increased MgSt concentration or increased solid fraction. These data suggest a non-linear relationship, but additional experiments are necessary to investigate this hypothesis. Optimizing sticking characteristics is not as simple as merely increasing MgSt concentrations and solid fractions. In fact, increased MgSt concentration and solid fraction are not always the best remedy for a sticking problem. Increased MgSt concentration can lead to lower tablet hardness at a given compression force and can lead to wetting, disintegration and flow problems [15]. High solid fraction can also lead to unacceptable disintegration and, in conjunction with high MgSt concentration, can lead to tablet capping. The data presented here allow an evaluation of the sensitivity of a particular formulation to lubricant level and tabletting parameters. This information, in conjunction with evaluation of the properties of the resulting tablets, allows for a more informed decision regarding how to address sticking issues Reproducibility and generality of the method One of the goals at the outset of these studies was to develop a reliable, reproducible and material sparing method to quantify tablet sticking. Evaluation of some of the early results allowed the method to be optimized to address these goals. During the early development of the method on the rotary tablet press, runs of 2500, 5000 and 7000 cycles, starting with five punch sets, were carried out. This corresponds to a total of 6750, 9750 and 16,500 tablets, respectively (Figs. 4 and 6a). Based on the initial results, the method was modified to utilize four punch sets and a maximum of 3000 cycles, resulting in a total of 6500 tablets per experiment (Figs. 5, 6b and c). In all cases, there was good linearity. In an effort to further reduce the amount of API necessary and to evaluate reproducibility, a run was carried out with Formulation III compressed at 82% solid fraction for 1250 cycles with punches removed at 500, 750 and 1000 cycles. The total number of tablets produced using this design is The results from this run were compared to previous runs using the same formulation and processing conditions (see Figs. 4 and 6a). The results are shown in Fig. 12 and a comparison of the slopes, with associated slope errors, is shown in Fig. 16. Although these runs were carried out at different times with different lots of blend and to different numbers of cycles, the slopes of the layering lines are the same within experimental error. Limiting the runs to 1250 cycles allows the complete experiment to be carried out with less than 500 g of blend without impacting the results. The initial development and optimization of the method were carried out using ABT-089 as a model compound. One of the key questions regarding the method is its generality. The method was

10 T.S. McDermott et al. / Powder Technology 212 (2011) Fig. 13. Photos of lower and upper punches ranging from 0 to 1250 cycles for Formulation III (20% ABT-089/0.75% MgSt) compressed to 82% solid fraction. demonstrated using a different API, ABT-279. Formulation VI (5% ABT- 279 in a standard blend) was compressed to 82% solid fraction and the punches were extracted as described previously. As was seen with ABT-089, there was a linear increase in API layering with the number of cycles (r 2 =0.9954). This blend showed a shallow slope and a relatively small amount of API layered on the punches even after 5000 cycles (about 0.1 mg). However, analysis of the entire data set showed that ABT-279 layering increased as the run continued, leading to concern about moving to higher drug load or longer compression times. Indeed, doubling the drug load to 10% (Formulation VII) led to a 24-fold increase in the slope of the layering line (Fig. 9) Characterization of adhered material The studies presented above demonstrated that by measuring the amount of API adhered to the punch faces it is possible to discriminate

11 250 T.S. McDermott et al. / Powder Technology 212 (2011) Fig. 14. A plot of layering line slope from Fig. 5 versus MgSt concentration for a series of blends compressed to 82% solid fraction. There is a decrease in slope with increasing MgSt concentration (r 2 =0.9759). The regression line is drawn for illustration purposes and not as a model. Fig. 16. Comparison of layering line slopes for a series of runs of Formulation III (20% ABT-089/0.75% MgSt) compressed to 82% solid fraction. The error bars are the error associated with the least square fit slope value. The slopes are the same within experimental error. between the sticking tendencies of different blends and materials compressed to different solid fractions. The working assumption was that the API selectively adheres to the punch faces and is responsible for the observed sticking. However, the API quantitation method does not allow determination of the exact makeup of the adhered material. SEM/EDS analysis was used to localize specific elements in order to identify the material adhered to the punch face and to compare to the corresponding blend. The EDS map for each element shows a dark background and bright spots that indicate high concentrations of the element of interest. For nitrogen maps (ABT-089), there is poor contrast between the background and the positive signals. This appearance is the result of the inherent noise in the nitrogen measurement and the small particle size of the API. The SEM/EDS data for a hand-pressed compact of Formulation III and for a lower punch after compression of Formulation III to 82% solid fraction for 3000 cycles are shown in Figs. 7 and 8, respectively. In the blend compact (Fig. 7), the API appears as loose aggregates of high concentration, but the other components appear as primary particles (CC) or well-defined agglomerates (SiO 2 and MgSt). On the punch face (Fig. 8), the API still appears as a well-distributed uniform layer and the overall amount appears greater (fewer dark regions). However, there is a marked difference in the appearance of the excipients. The SiO 2 and MgSt that are present on the punch face after Fig. 15. A plot of layering line slope from Fig. 6c versus solid fraction for Formulation V (20% ABT-089/1.25% MgSt) compressed to different solid fractions. There is a decrease in slope with increasing solid fraction (r 2 =0.9544). The regression line is drawn for illustration purposes and not as a model. compression appear more finely distributed across the punch face surface. The amount of SiO 2 appears to be increased on the punch face relative to the blend. There was very little CC present in the material adhered to the punch face. Visualization of the blend and the punch face by SEM/EDS gives a qualitative picture of the morphological differences. However, the technique can also be used to obtain a more quantitative assessment. All emission data used to construct the EDS images can be summed and presented as a single spectrum. For ABT-089, spectra from the blend compact and from the punch face are overlaid in Fig. 17. This allows the concentration of each formulation component on the punch face to be compared directly to the corresponding blend. There is a clear increase in the concentration of nitrogen detected on the punch face relative to the blend indicating an increase in the amount of API. As a further verification of the increase in API on the punch tip, the adhered material from one of the punch sets from this experiment was scraped from the punch tips, weighed and analyzed for ABT-089. HPLC analysis showed the material to be 71% ABT-089 compared to 20% in the starting blend. The concentration of MgSt on the punch face was about the same as in the blend and there was very little CC detected on the punch face. Surprisingly, the concentration of SiO 2 on the punch face was significantly increased relative to the blend. The large SiO 2 agglomerates seen in the SEM images of the blend compact are consistent with what has been reported in the literature for hydrophilic SiO 2 [16]. Because of their soft nature, these agglomerates readily transfer material to the punch during compression leading to the observed fine distribution of SiO 2 on the punch face. Unlike the soft agglomerates, the finely distributed SiO 2 does not transfer back to the tablet during compression, resulting in a unidirectional transfer of material from the blend to the punch face surface. A more thorough investigation of the effect of SiO 2 on sticking is underway. A similar analysis was carried out for ABT-279. In the SEM/EDS images of the blend and punch (Figs. 10 and 11, respectively) the API appears as a relatively even distribution of agglomerates or small particles while the CC appears as primary particles. MgSt and SiO 2 appear as a mixture of large and small agglomerates. A comparison of the summation of EDS spectra for the blend and punch is shown in Fig. 18. As was seen with ABT-089, the punch face showed increased concentrations of API and SiO 2. The concentration of MgSt was about the same on the punch face and in the blend and there was little or no CC detected on the punch face. As a further verification of the increase in API on the punch face, the adhered material from one of the punch sets from this experiment was scraped from the punch tips, weighed and analyzed for ABT-279. HPLC analysis showed the material to be 55% ABT-279 compared to 10% in the starting blend.

12 T.S. McDermott et al. / Powder Technology 212 (2011) Fig. 17. Comparison of EDS spectra for a hand-compressed compact of Formulation III (solid) and the lower punch face after compression of Formulation III to 82% solid fraction for 3000 cycles (black line). Fig. 18. Comparison of EDS spectra for a hand-compressed compact of Formulation VII (solid) and the lower punch face (black line) after compression of Formulation VII to 85% solid fraction for 1250 cycles. 5. Conclusion We have detailed a method to directly measure the API adhered to standard tablet punch surfaces after compression and showed that the amount of API adhered to the punch faces increases linearly with the number of tabletting cycles for two model compounds, ABT-089 and ABT-279. SEM/EDS analysis was used to characterize the material on the punch face and in the corresponding blend. In the blend, MgSt and SiO 2 were present as relatively large agglomerates. On the surface of the punch, API, MgSt and SiO 2 were evenly distributed and the concentrations of API and SiO 2 were increased relative to the blend. A series of studies was carried out to determine the sensitivity of the method to formulation and processing changes. The method was used demonstrate that different grades of MCC lead to different layering behavior making the method ideal for excipient screening. The method was used to quantitatively measure the influence of solid fraction and MgSt concentration on punch layering. Increased solid fraction and increased MgSt concentration led to decreased API

13 252 T.S. McDermott et al. / Powder Technology 212 (2011) layering. After establishment of the method on a single punch press, a much more efficient protocol was developed using a rotary press. Finally, it was demonstrated that as little as 500 g of blend is necessary to evaluate sticking tendency under real-world conditions. Acknowledgments The authors thank Dr. Martin Bultmann and Professor George Zografi for useful discussion regarding this work. Anthony Hlinak received a B.S. in Mechanical Engineering from Northwestern University (Evanston, IL) in 1974, an M.S. in Mechanical Engineering from the University of California at Berkeley in 1975, and an M.S. in Materials Science and Engineering from Northwestern in He has held positions of increasing responsibility since joining the Pharmaceutical Industry in 1983, including Section Head Formulation and Technology at Searle, Director Global External Supply at Pharmacia, and Director Global Formulation Sciences at Abbott. He is currently an independent consultant focused on sourcing strategies, technology development and transfer, technical problem solving, and process modeling projects. References [1] J.J. Wang, T. Li, S.D. Bateman, R. Erck, K.R. Morris, Modeling of adhesion in tablet compression I. Atomic force microscopy and molecular simulation, J. Pharm. Sci. 92 (2003) [2] M. Roberts, J.L. Ford, G.S. MacLeod, J.T. Fell, G.W. Smith, P.H. Rowe, Effects of surface roughness and chrome plating of punch tips on the sticking tendencies of model ibuprofen formulations, J. Pharm. Pharmacol. 55 (2003) [3] M. Roberts, J.L. Ford, G.S. MacLeod, J.T. Fell, G.W. Smith, P.H. Rowe, A.M. Dyas, Effect of lubricant type and concentration on the punch tip adherence of model ibuprofen formulations, J. Pharm. Pharmacol. 56 (2003) [4] M. Roberts, J.L. Ford, G.S. MacLeod, J.T. Fell, G.W. Smith, P.H. Rowe, A.M. Dyas, Effect of punch tip geometry and embossment on the punch tip adherence of a model ibuprofen formulation, J. Pharm. Pharmacol. 56 (2004) [5] F. Waimer, M. Krumme, P. Danz, U. Tenter, P.C. Wchmidt, A novel method for the detection of sticking of tablets, Pharm. Dev. Tech. 4 (1999) [6] Y. Shimada, Y. Yonezawa, H. Sunada, Measurement and evaluation of the adhesive force between particles by the direct separation method, J. Pharm. Sci. 92 (2003) [7] S.I. Naito, K. Masui, T. Shiraki, Prediction of tableting problems such as capping and sticking: theoretical calculations, J. Pharm. Sci. 66 (1977) [8] A. Mitrevej, L.L. Augsburger, Adhesion of tablets in a rotary tablet press. II. Effects of blending time, running time, and lubricant concentration, Drug Dev. Ind. Pharm. 8 (1982) [9] M.D. Tousey, Tablet Press Operation. Tablets & Capsules. October, www. tabletscapsules.com [10] There are two additional internal Abbott compounds for which this relationship has been observed. [11] M.P. Mullarney, B.C. Hancock, Mechanical property anisotropy of pharmaceutical excipient compacts, Int. J. Pharm. 314 (2006) [12] A. Sabir, B. Evans, S. Jain, Formulation and process optimization to eliminate picking from market image tablets, Int. J. Pharm. 215 (2001) [13] A. Mehrotra, M. Llusa, A. Faqih, M. Levin, F.J. Muzzio, Influence of shear intensity and total shear on properties of blends and tablets of lactose and cellulose lubricated with magnesium stearate, Int. J. Pharm. 336 (2007) [14] D. Weber, Y. Pu, C.L. Cooney, Quantification of lubricant activity of magnesium stearate by atomic force microscopy, Drug Dev. Ind. Pharm. 34 (2008) [15] K.P. Rao, G. Chawla, A.M. Kaushal, A.K. Bansal, Impact of solid-state properties on lubrication efficacyofmagnesium stearate, Pharm. Dev. Technol. 10 (2005) [16] S. Jonat, S. Hasenzahl, A. Gray, P.C. Schmidt, Mechanism of glidants: investigation of the effect of different colloidal silicon dioxide types on powder flow by atomic force and scanning electron microscopy, J. Pharm. Sci. 93 (2004) Joseph P. Neilly received a B.S. in Biology in 1979 and a M.S. in Bioengineering in 1983, both from University of Illinois at Chicago. He started his career at Baxter international as a research scientist in microscopy and microanalysis. He has worked at Abbott Laboratories for twenty-four years in areas of microscopy, microanalysis, forensic, science and pharmaceutical development and is currently the group leader of a microanalytical group that supports research, development and commercial aspects of the pharmaceutical and diagnostic divisions within Abbott. He is active in the Pharmaceutical focused interest group of the Microscopy Society of America (MSA) and the corporate liaison of the Midwest Microscopy and Microanalysis Society (MMMS). Dorothea Sauer earned her undergraduate degree in pharmacy from the Freie Universitat Berlin, Germany (2003) and her Ph.D. in Pharmaceutics from the University of Texas at Austin (2008). Following graduate school, she was working as a Research Scientist in the Global Formulation Sciences Group at Abbott Laboratories and investigated aspects of sticking and picking during tablet compression. She recently joined the Formulation and Process Development Group at Gilead Sciences, Inc. as a Research Scientist. Todd McDermott received a B.S. in Chemistry from Eastern Illinois in 1990 and a Ph.D. in Organic Chemistry from the University of California at Berkeley in Following graduate school, he was a NIH post-doctoral fellow at the University of Wisconsin, Madison. He joined the Process Chemistry group at Abbott in In 2008, he took his current position in Abbott's Global Formulation Sciences group. In addition to supporting projects at all stages of development, Todd heads an active research program studying the impact of particle particle interactions and surface properties on the behavior of APIs in blends. Jochen Farrenkopf received a Ph.D. in Pharmaceutical Technology from the University of Heidelberg (Germany) in His Ph.D. dissertation was based on roller compaction applications. Following school, he conducted a vocational training as Chemical Laboratory Assistant. In 1990, he joined the School of Pharmacy, University of Heidelberg. In 1997, he joined Abbott as Pharmacist and took his current position in the Global Formulation Sciences Solids in 2001 as group leader. In addition to supporting projects at all stages of development, Jochen passed the Postgraduate Education Academy of the Federal Chamber of Pharmacists, Germany.