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Mechanical Properties and Tableting Behavior of Amorphous Solid Dispersions
Journal of Pharmaceutical Sciences xxx (2016) 1-7
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Pharmaceutics, Drug Delivery and Pharmaceutical Technology
Mechanical Properties and Tableting Behavior of Amorphous Solid Dispersions Sarsvat Patel 1, Xiang Kou 1, Hao (Helen) Hou 2, Ye (Bill) Huang 2, John C. Strong 2, Geoff G.Z. Zhang 2, Changquan Calvin Sun 1, * 1 2
Pharmaceutical Materials Science & Engineering Laboratory, Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455 Drug Product Development, Research and Development, AbbVie Inc., North Chicago, Illinois 60064
a r t i c l e i n f o
a b s t r a c t
Article history: Received 8 April 2016 Revised 2 August 2016 Accepted 25 August 2016
Amorphous solid dispersions (ASDs) consisting of acetaminophen (APAP) and copovidone were systematically studied to identify effects of drug loading and moisture content on mechanical properties, thermal properties, and tableting behavior. ASDs containing APAP at different levels were prepared by film casting and characterized by differential scanning calorimetry and nanoindentation. The glass transition temperature (Tg) continuously decreased with increasing amount of APAP, but the hardness of ASDs was increased at a low APAP content and reduced at high APAP content. This in turn significantly influenced tablet quality. Water reduced both the hardness and Tg of ASDs, and the APAP loading level corresponding to the transition to the softening mechanism was lower at a higher relative humidity. Overall, the mechanical properties, rather than the thermal properties, better represent the plasticization/antiplasticization effect of small molecule to ASDs. © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
Keywords: amorphous compaction dispersion glass transition hardness mechanical properties physical characterization solid state tablet
Introduction Approximately 80% of new chemical entities are poorly soluble.1 If poor aqueous solubility limits the bioavailability of an active pharmaceutical ingredient (API), an appropriate solubilization technique must be applied for successful drug delivery. Among common solubilization techniques, amorphous solid dispersions (ASDs) have shown potential in improving the oral bioavailability of poorly soluble compounds.2-6
Conflicts of interest: University of Minnesota and AbbVie jointly participated in study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. Sarsvat Patel and Xiang Kou were postdocs at University of Minnesota, Changquan Calvin Sun is a professor at University of Minnesota, and Hao (Helen) Hou is an employee at Genentech Inc. None has additional conflicts of interest to report. Ye (Bill) Huang, John C. Strong, and Geoff G. Z. Zhang are employees of AbbVie Inc. and may own AbbVie stock. The authors Sarsvat Patel and Xiang Kou contributed to the work equally. Current address for Hou: Research and Early Development, Genentech Inc., South San Francisco, California 94080. * Correspondence to: Changquan Calvin Sun (Telephone: 612-624-3722; Fax: 612-626-2125). E-mail address: [email protected] (C.C. Sun).
ASD can be prepared using a number of processes, such as hotmelt extrusion and solvent evaporation. The hydrophilic carrier is more commonly a polymer4 but small molecules may also be used in pharmaceutical development of ASDs. In addition, surfactants may be incorporated to improve dissolution and processability. The presence of these excipients often dominates the observed physical properties, making them quite distinct from that of the pure amorphous drug. The properties of ASDs important to pharmaceutical development include physical and chemical stability, solubility, dissolution, bioavailability, and manufacturability. Previous work has mainly focused on demonstrating the potential of ASDs in improving drug bioavailability,2 homogeneity and physical stability,7 dissolution behavior,8 material properties and process relevant to ASD manufacturing,9,10 and drug-polymer miscibility.11,12 Although important to designing high-quality tablet formulations and robust manufacturing processes, the mechanical properties of ASD have rarely been studied. Lamm et al.13 systematically studied the impact of both clotrimazole and moisture on the hardness and elastic modulus of copovidone, that is, Kollidon VA 64. They found that ASDs were softened at a higher relative humidity (RH) and, at a given RH, the mechanical strength was the highest at an intermediate drug load. Such changes in the
http://dx.doi.org/10.1016/j.xphs.2016.08.021 0022-3549/© 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
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Scheme 1. Chemical structures of a) APAP and b) copovidone.
mechanical properties of ASD are expected to have an impact on tableting.13,14 Generally, the ratio of hydrophilic matrix to API in an ASD formulation is 4:1 or greater. A high ratio maintains the physical stability of the formulation particularly for APIs that tend to crystallize easily. However, much higher API loadings could be developed for poorly crystallizing APIs, provided the resulting ASD is physically stable.15 Often times, even for a relatively potent drug, the amount of ASD powder in a tablet is relatively high. Mechanical properties of ASD, therefore, will influence the compaction properties of the final formulation and the success of tablet manufacturing. In this context, knowledge of mechanical properties of ASDs is critical for their rapid development into high-quality tablets. Ideally, mechanical property characterization of ASD and its corresponding formulation blend should be an integral part of ASD formulation design and optimization, along with assessment of stability and dissolution performance. The objective of this work was to systematically examine the impact of drug loading and moisture on the mechanical properties and tableting performance of copovidone-based ASDs. Materials Acetaminophen (APAP; Scheme 1a) was purchased from SigmaAldrich. Copovidone, also known as PVP/VA 64 or Kollidon VA 64 (Scheme 1b), was a gift from BASF (Florham Park, NJ). The as-received copovidone contained 1.75% moisture. Methanol used in this work was HPLC grade (Fisher Chemical, Pittsburgh, PA).
depth to allow stress relaxation of plastic materials before withdrawal at 100 nm/s. Because the indentation depth is much smaller than 10% of the thickness of the films, the substrate effect can be ignored.16 At the same penetration depth, the maximum load will depend on the hardness of the sample. The stiffness of the unloading curve was derived from the force-displacement curve. Unloading data between 400 and 800 nm displacement were analyzed to obtain hardness, H, following the standard procedure.17 The area function of the probe tip was obtained by indenting a fused silica standard under a series of pressure. From the raw forcedisplacement data and the known modulus of fused silica, contact area is calculated. Such area function was then used to calculate hardness and elastic modulus of a sample from nanoindentation raw data. Performance of the nanoindenter was checked before and after analyzing each set of samples. It was deemed to function properly, if the elastic modulus was 70 ± 1 GPa. Temperature during the entire experiments was 20 C ± 0.5 C. The RH during nanoindentation was maintained by placing an appropriate saturated aqueous solution of different salts (LiCl, KC2H3O2, MgBr2, MgCl2, and NaBr) within the enclosure. Because the enclosure of the nanoindenter was not completely sealed, the RH differed slightly from that of the saturated salt solution, which was recorded continuously with an electronic RH sensor (Sensirion, Westlake Village, CA). Data collection was started when the RH within the enclosure was stable. The corresponding stable RH values were reported along with hardness data (n 9). Solid State Characterization of the ASDs
Methods Preparation of ASDs Appropriate amounts of APAP and copovidone were accurately weighed and dissolved in methanol. The total weight of dissolved solid was 10% (w/v), and the ratio of drug to polymer (corrected for moisture content) was varied to obtain ASDs containing 0%-40% (w/w) APAP. The solution was evenly spread on a glass slide using a pipette and air dried at ambient conditions for 30 min to form a viscous film. The film was subsequently dried in a 70 C oven for 90 min. The thickness of dried films was generally 100-200 mm as determined with a digital caliper. Before nanoindentation, the dried film was equilibrated overnight in an enclosed chamber at room temperature and a specified RH. Hardness Measurement by Nanoindentation Nanoindentation experiments were performed (NanoXP nanoindenter; MTS-Nano Instruments, Oak Ridge, TN) using a standard Berkovich diamond tip (tip radius z 100 nm with a total included angle of 142.3 and half angle of 65.3 ). The indenter tip was pressed into the film with a maximum travel distance of 1000 nm, speed of 100 nm/s, and a 10-s hold at the maximum penetration
Separately prepared films were examined by polarized light microscopy (Eclipse E200 POS; Nikon, Tokyo, Japan) to detect the presence of crystalline APAP. The physical stability of ASD, containing 0%-40% APAP, was also characterized using a powder X-ray diffractometer (D5005 Siemens) with CuKa radiation. Data were collected over a 5 -35 2q, using a step size of 0.02 and a dwell time of 1 s. To determine the glass transition temperature, Tg, a differential scanning calorimetry (DSC, model Q2000; TA Instruments, New Castle, DE) was used. Temperature and cell constant of the DSC were calibrated using an indium standard after performing baseline calibration. An aliquot of the ASD was transferred to an aluminum DSC pan and equilibrated at a desired RH at room temperature for 24 h. To measure the Tg of water-containing samples, equilibrated samples were hermetically sealed immediately after they were removed from the RH chamber. The sample weight was calculated from the total weight and weights of aluminum pan and lid. The sample was first thermally equilibrated at 50 C and then heated at a rate of 2 C/min to 130 C with an imposed sinusoidal modulation (±1 C every 100 s) and a nitrogen purge of 50 mL/min. To determine Tg of dry ASD, hermetic pans with a pin hole were used. ASD was first heated to 180 C to remove moisture, quenched to 50 C, and then heated in the same manner as that for wet
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Figure 1. Polarized light microscopic images of APAP-copovidone films. The width of each image is 1.3 mm.
A mixture of APAP in copovidone, containing 0%, 5%, and 15% of APAP, was extruded using a twin-screw extruder (Nano-16; Leistritz, Nuremberg, Germany). The extrudates were clear, and no APAP crystal was observed under polarized light microscope. The material was then milled using a high-speed food processor (KitchenAid) and sieved manually using a series of standard sieves. Three sieve cuts (75-125, 180-212, and 250-354 mm) were collected to assess the effect of particle size on tabletability. After storage in a 32% RH chamber containing a saturated MgCl2 solution for 24 h,
150-200 mg of each sieved powder was manually fed into a die and compressed at 100 MPa with a loading speed of 1 mm/min on a universal material testing machine (model 1485; Zwick/Roell, Kennesaw, GA). No hold at the maximum pressure was applied, and exposure of the powders to the ambient environment (27%-35% RH) was minimized. Three cylindrical tablets were made for each sieved powder using a flat-faced round tablet tooling (8 mm diameter). Before powder filling, both die and punch tips were coated with a suspension of magnesium stearate in ethanol (5%, w/v) and dried with a fan. The tablets were allowed to relax in a 32% RH chamber for 24 h and then were weighed (accurate to 0.1 mg) using an analytical balance (AG204; Mettler Toledo, Columbus, OH). Tablet thickness and diameter were measured using a digital caliper (World Precision Instruments, Sarasota, FL) with an accuracy of 10 mm. Allowed tablet thickness was in the range of 2.9-4.9 mm, depending on tablet weight and compaction pressure applied. Diametrical breaking force of individual tablets was measured using a texture analyzer (Texture Technologies Corporation, Scarsdale, NY), operated at a speed of 0.01 mm/s with a 5 g trigger force. Because all tablets failed diametrically in tension, tablet tensile strength could be calculated from tablet dimensions and breaking force as previously described.18-20
Figure 2. Powder X-ray diffraction of ASDs as a function of APAP loading in copovidone.
Figure 3. Moisture content of ASDs, equilibrated at 32% RH, as a function of APAP loading (n ¼ 3).
samples. Although both midpoint and onset Tg were obtained, only the onset Tg is reported. The moisture content was coulometrically determined in triplicate by Karl Fisher titration using a Mitsubishi Moisture Meter (model CA-05; Mitsubishi Chemical Industries Ltd., Tokyo, Japan). A blank run was carried out immediately before analysis of each sample, which were weighed on an analytical balance and quickly transferred to a titration vessel. The result from the blank run was used to correct for the effect of environment moisture on the measured water content in the sample. Tableting Performance
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was 55.6 C, which also decreased with increasing drug loading (Fig. 5a). At 30% drug loading, the Tg onset was 26.6 C, which was 6.6 C above room temperature at the time of nanoindentation experiments. However, at 40% APAP loading, the onset Tg was 16.5 C, which was below room temperature. When equilibrated at 57% RH, the onset Tg of copovidone (47.8 C) was lower than that at 32% RH. Tg also decreased with increasing drug loading and was below room temperature at 30% APAP loadings (Fig. 6a). Mechanical Properties and Tableting Performance
Figure 4. Tg of dry APAP-copovidone ASD as a function of APAP loading.
Results Solid State Properties of ASD ASDs containing 50% or more APAP are not included in this report, because they are not sufficiently stable for carrying out nanoindentation experiments due to phase separation or crystallization of APAP during preparation and storage. Films containing 0%-10% APAP cracked when the methanol was air dried but were free from cracks when containing 15%-40% APAP (Fig. 1). The powder X-ray diffraction patterns of ASD after storage at 32% RH for 48 h are presented in Figure 2. The film-casting step did not significantly change the X-ray diffraction pattern of copovidone. No diffraction peaks indicative of crystallinity were observed in any samples. The intensity of the amorphous halo of the polymer at 10 -17 2q gradually decreased with increasing APAP loading. Moisture content in ASD films, equilibrated at 32% RH, as a function of APAP loading is shown in Figure 3. With increasing APAP load, moisture content in ASD decreased nearly linearly from 5.8% for pure polymer to 3.9% for ASD containing 40% APAP. For a given sample, the onset Tg was 5 C-8 C below the corresponding midpoint Tg. The Tg of dry copovidone was 101 C, and the Tg of ASDs decreased nearly linearly with increasing APAP loading (Fig. 4). When equilibrated at 32% RH, the onset Tg of copovidone
For ASD films equilibrated at 32% RH, the hardness increased with increasing APAP loading up to 30% (w/w; Fig. 5b). The initial rate of increase was the greatest but gradually decreased with more APAP. At 40% loading, however, H abruptly decreased. For ASD films equilibrated at 57% RH, H slightly increased with APAP loading up to 15%, and then sharply decreased with further increases in APAP loading (Fig. 6b). We noted that the measured RH during nanoindentation experiment was 54% RH, likely due to slow escape of moisture from the nanoindenter enclosure. At a higher RH, H was always lower at the same APAP loading (Fig. 7). For ASD with the same APAP loading, the tensile strength of the tablets decreased with increasing particle size (Fig. 8a). At a comparable particle size, the incorporation of just 5% APAP caused a sharp decrease in tensile strength (Fig. 8). An increase in APAP from 5% to 15% resulted in further decrease in tablet tensile strength, although the magnitude was much smaller than that observed by the initial 5% addition of APAP. Discussion The observation of reduced water uptake by ASD at a higher APAP loading (Fig. 3) is consistent with the expected higher hydrophobicity of APAP relative to copovidone. The linear dependence suggests that the presence of APAP molecules may not significantly impact the interaction between water and copovidone, similar to physical mixtures. This is conceivable because water molecules, being much smaller than APAP, are more likely to interact with polymer molecules through hydrogen bonds. Had the molecules been much more hydrophobic or at a much higher APAP loading, the local chemical environment surrounding the polymer in the drug-polymer composite may be significantly different from that of the pure polymer. If so, nonlinear dependence of moisture content on drug loading should be observed.
Figure 5. Properties of APAP-copovidone ASD films equilibrated at 32% RH as a function of APAP loading: (a) onset Tg, with the dashed line indicating room temperature during nanoindentation experiments, and (b) hardness (n 9), which decreases sharply at 40% APAP.
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Figure 6. Properties of APAP-copovidone films equilibrated at 57% RH as a function of APAP loading: (a) Tg onset, with the dashed line indicating room temperature during nanoindentation experiments, and (b) hardness, which decreases sharply when Tg is close to room temperature. Error bars are smaller than the size of the symbols.
The presence of cracks in ASD films containing 10% APAP during air drying (Fig. 1) suggests that these films are brittle and unable to plastically relieve mechanical stress generated with methanol removal from the samples. The observation that films containing 15% APAP remain intact suggests that the ASDs were sufficiently ductile to relieve the stresses developed with drying. Cracking of amorphous films due to excessive stress developed on cooling has been studied.21 The plasticization effect is often identified by a reduction in Tg of ASD.3,22 In this work, the Tg of these ASDs at 0% RH decreased nearly linearly with increasing APAP loading (Fig. 4). Thus, APAP plasticizes copovidone based on measurement of Tg. For cracked films, nanoindentation was carried out in the areas free from cracks. The small relative standard deviation (<1%) in all measured H and the smooth trend (Fig. 7) suggest the cracks did not significantly affect the indentation measurements. The set of nanoindentation data at 32% RH (Fig. 5b) were collected within 1 day after samples were prepared. The absence of birefringence (Fig. 1) and X-ray diffraction peaks (Fig. 2) in these ASD samples, even after several days of storage, indicates that these ASD samples are physically stable in the timeframe of the nanoindentation experiments. Nanoindentation data show that APAP hardens
Figure 7. Hardness of APAP-copovidone ASD as a function of APAP loading and RH (n 9). Error bars are smaller than the size of the symbols.
copovidone up to 30% loading (Fig. 5b). Thus, in contrast to the Tg study, copovidone is antiplasticized by APAP at 30% concentration, based on the effect on mechanical strength. A similar hardening effect by APAP can be observed within the 11%-35% RH range (Fig. 7), confirming the antiplasticization effect by APAP. The phenomenon of antiplasticization of polymers by small molecules is known.15,23-26 Even the incorporation of a low level of water, commonly regarded as an effective plasticizer, leads to hardening and higher density of microcrystalline cellulose.20 Among the several mechanisms proposed to explain such antiplasticization phenomenon, the physically simple yet elegant space-filling mechanism is appealing.25,26 This mechanism only requires small molecules to fill the available free volumes in the polymer matrix with or without specific interactions. The seemingly conflicting effect of APAP on the ASD, that is, plasticization based on Tg and antiplasticization based on hardness, requires reconciliation. These 2 methods characterize 2 types of fundamentally different motion within the dispersion. Plastic deformation in hardness testing occurs by the coordinated movement of dislocations within the specimen under stress, whereas the glass transition corresponds to coordinated translation/rotation of segments of the polymer chains due to enhanced molecular mobility. When the mechanical properties are considered in the context of pharmaceutical manufacturing, the temperature is usually near 23 C (e.g., room temperature). Although Tg varies depending on the material, it is generally above room temperature for pharmaceutical ASDs. It is possible that a small molecule, such as APAP, can harden the polymer matrix at room temperature, while also reducing Tg of a polymer matrix provided that the Tg of the small molecule is lower than that of the polymer. This is because the smaller molecules have higher mobility than the polymer molecules at the same temperature. Hence, the composite undergoes a glass transition at a temperature below Tg of the pure polymer on account of the higher average molecular mobility. In this work, the Tg of APAP was 24 C, which is significantly lower than the Tg of the polymer (101 C in dry state and 55.6 C at 32% RH). Hence, the incorporation of APAP into copovidone is expected to reduce the Tg of the polymer at a fixed RH. In the context of tablet manufacturing, the relevant temperature usually does not significantly deviate from room temperature. Therefore, it is more appropriate to classify plasticization or antiplasticization effects of a small drug molecule on the polymer based on the induced mechanical properties rather than on Tg. By this criterion, APAP exhibits an antiplasticization effect on copovidone at a low APAP loading but plasticizes copovidone above a critical APAP loading.
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Figure 8. Tablet tensile strength (n ¼ 3) of APAP-copovidone ASDs containing 0%, 5%, and 15% APAP. Powders were equilibrated at 32% RH (a) as a function of particle size at 100 MPa compaction pressure; (b) as a function of tablet porosity for the 75-125 mm fraction. Lines were obtained by exponential fitting.
The abrupt reduction in H at 40% APAP at 32% RH (Fig. 5b) corresponds to the state when the onset Tg is below room temperature (Fig. 5a). At this composition, significant softening of the ASD is expected because it has transitioned from a glassy state to a rubbery state. To further test the relationship between onset Tg and softening, ASD films equilibrated at 57% RH were examined. At the same APAP loading, the higher water content at 57% RH further reduced the Tg of the ASDs by about 5 C-7 C (Figs. 5 and 6a). At 57% RH, the Tg of ASD is close to room temperature at 20% APAP loading and drops below room temperature at 30% APAP loading (Fig. 6a). Corresponding to the state when the onset Tg is below room temperature, H significantly decreases when APAP loading increases from 20% to 30% (Fig. 6b). In fact, at 40% APAP loading, the film is too soft to trigger the nanoindenter for data collection. Data at both 32% and 57% RHs support that the softening of ASD is correlated to its transition to a rubbery state. At an identical APAP loading, both Tg and H are always lower at a higher RH (Figs. 4-7). This observation supports the role of water as a plasticizer and is corroborated by the observed effect of RH on film cracking behavior, which depends not only on APAP content but also environment RH. For example, a crack-free film is obtained when copovidone methanol solution is air dried at 40% RH. However, when the same film is equilibrated at 30% RH or lower, visible and audible cracking takes place. This observation indicates that copovidone is brittle at 30% RH (~4.3% water). However, the amount of water (6.3%) at 40% RH sufficiently plasticizes copovidone film to avoid cracking at room temperature. The sensitivity of H to RH variations in the range of 11%-57% (Figs. 6 and 7) highlights the need to control RH to avoid compromising the robustness of manufacturing process and consistency in the quality of tablet products containing an ASD. At each of the 3 levels of APAP loading, the tablet tensile strength decreased with increasing particle size (Fig. 8a). This is expected because larger particles have smaller surface area available for interparticulate bonding within a tablet. In addition to the particle size effect, a change in the intrinsic mechanical properties of ASD is also expected to influence bulk powder compaction behavior. Harder particles are more resistant to permanent plastic deformation under pressure,27,28 which negatively impacts tabletability of ASD powders by reducing the bonding area developed during compression. In fact, the tensile strength of tablets compressed at 100 MPa decreased significantly when 5% APAP was added to copovidone (Fig. 8a). Although the use of 15% APAP leads to a further reduction in tablet tensile strength, the reduction is minor in comparison to that of adding 5% APAP
(Fig. 8a). In any case, tablet tensile strength of ASD is deteriorated by the addition of APAP when the particle size effect is excluded. Tablet tensile strength decreased exponentially with increasing tablet porosity, consistent with the Ryshkewitch-Duckworth relationship29 (Fig. 8b). At a given porosity, including zero porosity, tablet tensile strength decreased with increasing APAP loading. Thus, the bonding strength between ASD particles is lower at a higher APAP loading between 0% and 15%. Regardless of the exact mechanism by which APAP incorporation reduced hardness, early access to this information would be extremely helpful to formulation scientists for designing robust ASD tablet formulations and manufacturing processes because mechanical properties of ASD are expected to play an important role in the tableting behaviors of formulations. For an ASD with deficiencies in mechanical properties, it is critical to choose suitable excipients during the formulation development to overcome such a challenge. Conclusions The mechanical properties of APAP-copovidone ASDs are sensitive to both moisture content and APAP loading. The incorporation of APAP initially hardens ASD through the process of filling the interstitial space. However, APAP also depresses Tg of ASD. ASD is softened when a sufficient amount of APAP depresses the Tg to below room temperature. Higher moisture content leads to both lower Tg and softer ASD at the same APAP loading. A clear understanding of the complex effect of APAP requires the considerations of both mechanical and thermal properties. We suggest that the mechanical properties, instead of Tg, should be used to classify plasticization/antiplasticization effects by a small molecule. We have also demonstrated that hardening of ASD by APAP impacts the tableting performance of ASD powders. Acknowledgments We thank Dr. Sathyanarayana R. Perumalla for technical support in characterizing solid state properties of ASD samples. This work was supported by a grant from AbbVie. References 1. Takagi T, Ramachandran C, Bermejo M, Yamashita S, Yu LX, Amidon GL. A provisional biopharmaceutical classification of the top 200 oral drug
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Pharmaceutics, Drug Delivery and Pharmaceutical Technology
Mechanical Properties and Tableting Behavior of Amorphous Solid Dispersions Sarsvat Patel 1, Xiang Kou 1, Hao (Helen) Hou 2, Ye (Bill) Huang 2, John C. Strong 2, Geoff G.Z. Zhang 2, Changquan Calvin Sun 1, * 1 2
Pharmaceutical Materials Science & Engineering Laboratory, Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455 Drug Product Development, Research and Development, AbbVie Inc., North Chicago, Illinois 60064
a r t i c l e i n f o
a b s t r a c t
Article history: Received 8 April 2016 Revised 2 August 2016 Accepted 25 August 2016
Amorphous solid dispersions (ASDs) consisting of acetaminophen (APAP) and copovidone were systematically studied to identify effects of drug loading and moisture content on mechanical properties, thermal properties, and tableting behavior. ASDs containing APAP at different levels were prepared by film casting and characterized by differential scanning calorimetry and nanoindentation. The glass transition temperature (Tg) continuously decreased with increasing amount of APAP, but the hardness of ASDs was increased at a low APAP content and reduced at high APAP content. This in turn significantly influenced tablet quality. Water reduced both the hardness and Tg of ASDs, and the APAP loading level corresponding to the transition to the softening mechanism was lower at a higher relative humidity. Overall, the mechanical properties, rather than the thermal properties, better represent the plasticization/antiplasticization effect of small molecule to ASDs. © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
Keywords: amorphous compaction dispersion glass transition hardness mechanical properties physical characterization solid state tablet
Introduction Approximately 80% of new chemical entities are poorly soluble.1 If poor aqueous solubility limits the bioavailability of an active pharmaceutical ingredient (API), an appropriate solubilization technique must be applied for successful drug delivery. Among common solubilization techniques, amorphous solid dispersions (ASDs) have shown potential in improving the oral bioavailability of poorly soluble compounds.2-6
Conflicts of interest: University of Minnesota and AbbVie jointly participated in study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. Sarsvat Patel and Xiang Kou were postdocs at University of Minnesota, Changquan Calvin Sun is a professor at University of Minnesota, and Hao (Helen) Hou is an employee at Genentech Inc. None has additional conflicts of interest to report. Ye (Bill) Huang, John C. Strong, and Geoff G. Z. Zhang are employees of AbbVie Inc. and may own AbbVie stock. The authors Sarsvat Patel and Xiang Kou contributed to the work equally. Current address for Hou: Research and Early Development, Genentech Inc., South San Francisco, California 94080. * Correspondence to: Changquan Calvin Sun (Telephone: 612-624-3722; Fax: 612-626-2125). E-mail address: [email protected] (C.C. Sun).
ASD can be prepared using a number of processes, such as hotmelt extrusion and solvent evaporation. The hydrophilic carrier is more commonly a polymer4 but small molecules may also be used in pharmaceutical development of ASDs. In addition, surfactants may be incorporated to improve dissolution and processability. The presence of these excipients often dominates the observed physical properties, making them quite distinct from that of the pure amorphous drug. The properties of ASDs important to pharmaceutical development include physical and chemical stability, solubility, dissolution, bioavailability, and manufacturability. Previous work has mainly focused on demonstrating the potential of ASDs in improving drug bioavailability,2 homogeneity and physical stability,7 dissolution behavior,8 material properties and process relevant to ASD manufacturing,9,10 and drug-polymer miscibility.11,12 Although important to designing high-quality tablet formulations and robust manufacturing processes, the mechanical properties of ASD have rarely been studied. Lamm et al.13 systematically studied the impact of both clotrimazole and moisture on the hardness and elastic modulus of copovidone, that is, Kollidon VA 64. They found that ASDs were softened at a higher relative humidity (RH) and, at a given RH, the mechanical strength was the highest at an intermediate drug load. Such changes in the
http://dx.doi.org/10.1016/j.xphs.2016.08.021 0022-3549/© 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.
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Scheme 1. Chemical structures of a) APAP and b) copovidone.
mechanical properties of ASD are expected to have an impact on tableting.13,14 Generally, the ratio of hydrophilic matrix to API in an ASD formulation is 4:1 or greater. A high ratio maintains the physical stability of the formulation particularly for APIs that tend to crystallize easily. However, much higher API loadings could be developed for poorly crystallizing APIs, provided the resulting ASD is physically stable.15 Often times, even for a relatively potent drug, the amount of ASD powder in a tablet is relatively high. Mechanical properties of ASD, therefore, will influence the compaction properties of the final formulation and the success of tablet manufacturing. In this context, knowledge of mechanical properties of ASDs is critical for their rapid development into high-quality tablets. Ideally, mechanical property characterization of ASD and its corresponding formulation blend should be an integral part of ASD formulation design and optimization, along with assessment of stability and dissolution performance. The objective of this work was to systematically examine the impact of drug loading and moisture on the mechanical properties and tableting performance of copovidone-based ASDs. Materials Acetaminophen (APAP; Scheme 1a) was purchased from SigmaAldrich. Copovidone, also known as PVP/VA 64 or Kollidon VA 64 (Scheme 1b), was a gift from BASF (Florham Park, NJ). The as-received copovidone contained 1.75% moisture. Methanol used in this work was HPLC grade (Fisher Chemical, Pittsburgh, PA).
depth to allow stress relaxation of plastic materials before withdrawal at 100 nm/s. Because the indentation depth is much smaller than 10% of the thickness of the films, the substrate effect can be ignored.16 At the same penetration depth, the maximum load will depend on the hardness of the sample. The stiffness of the unloading curve was derived from the force-displacement curve. Unloading data between 400 and 800 nm displacement were analyzed to obtain hardness, H, following the standard procedure.17 The area function of the probe tip was obtained by indenting a fused silica standard under a series of pressure. From the raw forcedisplacement data and the known modulus of fused silica, contact area is calculated. Such area function was then used to calculate hardness and elastic modulus of a sample from nanoindentation raw data. Performance of the nanoindenter was checked before and after analyzing each set of samples. It was deemed to function properly, if the elastic modulus was 70 ± 1 GPa. Temperature during the entire experiments was 20 C ± 0.5 C. The RH during nanoindentation was maintained by placing an appropriate saturated aqueous solution of different salts (LiCl, KC2H3O2, MgBr2, MgCl2, and NaBr) within the enclosure. Because the enclosure of the nanoindenter was not completely sealed, the RH differed slightly from that of the saturated salt solution, which was recorded continuously with an electronic RH sensor (Sensirion, Westlake Village, CA). Data collection was started when the RH within the enclosure was stable. The corresponding stable RH values were reported along with hardness data (n 9). Solid State Characterization of the ASDs
Methods Preparation of ASDs Appropriate amounts of APAP and copovidone were accurately weighed and dissolved in methanol. The total weight of dissolved solid was 10% (w/v), and the ratio of drug to polymer (corrected for moisture content) was varied to obtain ASDs containing 0%-40% (w/w) APAP. The solution was evenly spread on a glass slide using a pipette and air dried at ambient conditions for 30 min to form a viscous film. The film was subsequently dried in a 70 C oven for 90 min. The thickness of dried films was generally 100-200 mm as determined with a digital caliper. Before nanoindentation, the dried film was equilibrated overnight in an enclosed chamber at room temperature and a specified RH. Hardness Measurement by Nanoindentation Nanoindentation experiments were performed (NanoXP nanoindenter; MTS-Nano Instruments, Oak Ridge, TN) using a standard Berkovich diamond tip (tip radius z 100 nm with a total included angle of 142.3 and half angle of 65.3 ). The indenter tip was pressed into the film with a maximum travel distance of 1000 nm, speed of 100 nm/s, and a 10-s hold at the maximum penetration
Separately prepared films were examined by polarized light microscopy (Eclipse E200 POS; Nikon, Tokyo, Japan) to detect the presence of crystalline APAP. The physical stability of ASD, containing 0%-40% APAP, was also characterized using a powder X-ray diffractometer (D5005 Siemens) with CuKa radiation. Data were collected over a 5 -35 2q, using a step size of 0.02 and a dwell time of 1 s. To determine the glass transition temperature, Tg, a differential scanning calorimetry (DSC, model Q2000; TA Instruments, New Castle, DE) was used. Temperature and cell constant of the DSC were calibrated using an indium standard after performing baseline calibration. An aliquot of the ASD was transferred to an aluminum DSC pan and equilibrated at a desired RH at room temperature for 24 h. To measure the Tg of water-containing samples, equilibrated samples were hermetically sealed immediately after they were removed from the RH chamber. The sample weight was calculated from the total weight and weights of aluminum pan and lid. The sample was first thermally equilibrated at 50 C and then heated at a rate of 2 C/min to 130 C with an imposed sinusoidal modulation (±1 C every 100 s) and a nitrogen purge of 50 mL/min. To determine Tg of dry ASD, hermetic pans with a pin hole were used. ASD was first heated to 180 C to remove moisture, quenched to 50 C, and then heated in the same manner as that for wet
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Figure 1. Polarized light microscopic images of APAP-copovidone films. The width of each image is 1.3 mm.
A mixture of APAP in copovidone, containing 0%, 5%, and 15% of APAP, was extruded using a twin-screw extruder (Nano-16; Leistritz, Nuremberg, Germany). The extrudates were clear, and no APAP crystal was observed under polarized light microscope. The material was then milled using a high-speed food processor (KitchenAid) and sieved manually using a series of standard sieves. Three sieve cuts (75-125, 180-212, and 250-354 mm) were collected to assess the effect of particle size on tabletability. After storage in a 32% RH chamber containing a saturated MgCl2 solution for 24 h,
150-200 mg of each sieved powder was manually fed into a die and compressed at 100 MPa with a loading speed of 1 mm/min on a universal material testing machine (model 1485; Zwick/Roell, Kennesaw, GA). No hold at the maximum pressure was applied, and exposure of the powders to the ambient environment (27%-35% RH) was minimized. Three cylindrical tablets were made for each sieved powder using a flat-faced round tablet tooling (8 mm diameter). Before powder filling, both die and punch tips were coated with a suspension of magnesium stearate in ethanol (5%, w/v) and dried with a fan. The tablets were allowed to relax in a 32% RH chamber for 24 h and then were weighed (accurate to 0.1 mg) using an analytical balance (AG204; Mettler Toledo, Columbus, OH). Tablet thickness and diameter were measured using a digital caliper (World Precision Instruments, Sarasota, FL) with an accuracy of 10 mm. Allowed tablet thickness was in the range of 2.9-4.9 mm, depending on tablet weight and compaction pressure applied. Diametrical breaking force of individual tablets was measured using a texture analyzer (Texture Technologies Corporation, Scarsdale, NY), operated at a speed of 0.01 mm/s with a 5 g trigger force. Because all tablets failed diametrically in tension, tablet tensile strength could be calculated from tablet dimensions and breaking force as previously described.18-20
Figure 2. Powder X-ray diffraction of ASDs as a function of APAP loading in copovidone.
Figure 3. Moisture content of ASDs, equilibrated at 32% RH, as a function of APAP loading (n ¼ 3).
samples. Although both midpoint and onset Tg were obtained, only the onset Tg is reported. The moisture content was coulometrically determined in triplicate by Karl Fisher titration using a Mitsubishi Moisture Meter (model CA-05; Mitsubishi Chemical Industries Ltd., Tokyo, Japan). A blank run was carried out immediately before analysis of each sample, which were weighed on an analytical balance and quickly transferred to a titration vessel. The result from the blank run was used to correct for the effect of environment moisture on the measured water content in the sample. Tableting Performance
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was 55.6 C, which also decreased with increasing drug loading (Fig. 5a). At 30% drug loading, the Tg onset was 26.6 C, which was 6.6 C above room temperature at the time of nanoindentation experiments. However, at 40% APAP loading, the onset Tg was 16.5 C, which was below room temperature. When equilibrated at 57% RH, the onset Tg of copovidone (47.8 C) was lower than that at 32% RH. Tg also decreased with increasing drug loading and was below room temperature at 30% APAP loadings (Fig. 6a). Mechanical Properties and Tableting Performance
Figure 4. Tg of dry APAP-copovidone ASD as a function of APAP loading.
Results Solid State Properties of ASD ASDs containing 50% or more APAP are not included in this report, because they are not sufficiently stable for carrying out nanoindentation experiments due to phase separation or crystallization of APAP during preparation and storage. Films containing 0%-10% APAP cracked when the methanol was air dried but were free from cracks when containing 15%-40% APAP (Fig. 1). The powder X-ray diffraction patterns of ASD after storage at 32% RH for 48 h are presented in Figure 2. The film-casting step did not significantly change the X-ray diffraction pattern of copovidone. No diffraction peaks indicative of crystallinity were observed in any samples. The intensity of the amorphous halo of the polymer at 10 -17 2q gradually decreased with increasing APAP loading. Moisture content in ASD films, equilibrated at 32% RH, as a function of APAP loading is shown in Figure 3. With increasing APAP load, moisture content in ASD decreased nearly linearly from 5.8% for pure polymer to 3.9% for ASD containing 40% APAP. For a given sample, the onset Tg was 5 C-8 C below the corresponding midpoint Tg. The Tg of dry copovidone was 101 C, and the Tg of ASDs decreased nearly linearly with increasing APAP loading (Fig. 4). When equilibrated at 32% RH, the onset Tg of copovidone
For ASD films equilibrated at 32% RH, the hardness increased with increasing APAP loading up to 30% (w/w; Fig. 5b). The initial rate of increase was the greatest but gradually decreased with more APAP. At 40% loading, however, H abruptly decreased. For ASD films equilibrated at 57% RH, H slightly increased with APAP loading up to 15%, and then sharply decreased with further increases in APAP loading (Fig. 6b). We noted that the measured RH during nanoindentation experiment was 54% RH, likely due to slow escape of moisture from the nanoindenter enclosure. At a higher RH, H was always lower at the same APAP loading (Fig. 7). For ASD with the same APAP loading, the tensile strength of the tablets decreased with increasing particle size (Fig. 8a). At a comparable particle size, the incorporation of just 5% APAP caused a sharp decrease in tensile strength (Fig. 8). An increase in APAP from 5% to 15% resulted in further decrease in tablet tensile strength, although the magnitude was much smaller than that observed by the initial 5% addition of APAP. Discussion The observation of reduced water uptake by ASD at a higher APAP loading (Fig. 3) is consistent with the expected higher hydrophobicity of APAP relative to copovidone. The linear dependence suggests that the presence of APAP molecules may not significantly impact the interaction between water and copovidone, similar to physical mixtures. This is conceivable because water molecules, being much smaller than APAP, are more likely to interact with polymer molecules through hydrogen bonds. Had the molecules been much more hydrophobic or at a much higher APAP loading, the local chemical environment surrounding the polymer in the drug-polymer composite may be significantly different from that of the pure polymer. If so, nonlinear dependence of moisture content on drug loading should be observed.
Figure 5. Properties of APAP-copovidone ASD films equilibrated at 32% RH as a function of APAP loading: (a) onset Tg, with the dashed line indicating room temperature during nanoindentation experiments, and (b) hardness (n 9), which decreases sharply at 40% APAP.
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Figure 6. Properties of APAP-copovidone films equilibrated at 57% RH as a function of APAP loading: (a) Tg onset, with the dashed line indicating room temperature during nanoindentation experiments, and (b) hardness, which decreases sharply when Tg is close to room temperature. Error bars are smaller than the size of the symbols.
The presence of cracks in ASD films containing 10% APAP during air drying (Fig. 1) suggests that these films are brittle and unable to plastically relieve mechanical stress generated with methanol removal from the samples. The observation that films containing 15% APAP remain intact suggests that the ASDs were sufficiently ductile to relieve the stresses developed with drying. Cracking of amorphous films due to excessive stress developed on cooling has been studied.21 The plasticization effect is often identified by a reduction in Tg of ASD.3,22 In this work, the Tg of these ASDs at 0% RH decreased nearly linearly with increasing APAP loading (Fig. 4). Thus, APAP plasticizes copovidone based on measurement of Tg. For cracked films, nanoindentation was carried out in the areas free from cracks. The small relative standard deviation (<1%) in all measured H and the smooth trend (Fig. 7) suggest the cracks did not significantly affect the indentation measurements. The set of nanoindentation data at 32% RH (Fig. 5b) were collected within 1 day after samples were prepared. The absence of birefringence (Fig. 1) and X-ray diffraction peaks (Fig. 2) in these ASD samples, even after several days of storage, indicates that these ASD samples are physically stable in the timeframe of the nanoindentation experiments. Nanoindentation data show that APAP hardens
Figure 7. Hardness of APAP-copovidone ASD as a function of APAP loading and RH (n 9). Error bars are smaller than the size of the symbols.
copovidone up to 30% loading (Fig. 5b). Thus, in contrast to the Tg study, copovidone is antiplasticized by APAP at 30% concentration, based on the effect on mechanical strength. A similar hardening effect by APAP can be observed within the 11%-35% RH range (Fig. 7), confirming the antiplasticization effect by APAP. The phenomenon of antiplasticization of polymers by small molecules is known.15,23-26 Even the incorporation of a low level of water, commonly regarded as an effective plasticizer, leads to hardening and higher density of microcrystalline cellulose.20 Among the several mechanisms proposed to explain such antiplasticization phenomenon, the physically simple yet elegant space-filling mechanism is appealing.25,26 This mechanism only requires small molecules to fill the available free volumes in the polymer matrix with or without specific interactions. The seemingly conflicting effect of APAP on the ASD, that is, plasticization based on Tg and antiplasticization based on hardness, requires reconciliation. These 2 methods characterize 2 types of fundamentally different motion within the dispersion. Plastic deformation in hardness testing occurs by the coordinated movement of dislocations within the specimen under stress, whereas the glass transition corresponds to coordinated translation/rotation of segments of the polymer chains due to enhanced molecular mobility. When the mechanical properties are considered in the context of pharmaceutical manufacturing, the temperature is usually near 23 C (e.g., room temperature). Although Tg varies depending on the material, it is generally above room temperature for pharmaceutical ASDs. It is possible that a small molecule, such as APAP, can harden the polymer matrix at room temperature, while also reducing Tg of a polymer matrix provided that the Tg of the small molecule is lower than that of the polymer. This is because the smaller molecules have higher mobility than the polymer molecules at the same temperature. Hence, the composite undergoes a glass transition at a temperature below Tg of the pure polymer on account of the higher average molecular mobility. In this work, the Tg of APAP was 24 C, which is significantly lower than the Tg of the polymer (101 C in dry state and 55.6 C at 32% RH). Hence, the incorporation of APAP into copovidone is expected to reduce the Tg of the polymer at a fixed RH. In the context of tablet manufacturing, the relevant temperature usually does not significantly deviate from room temperature. Therefore, it is more appropriate to classify plasticization or antiplasticization effects of a small drug molecule on the polymer based on the induced mechanical properties rather than on Tg. By this criterion, APAP exhibits an antiplasticization effect on copovidone at a low APAP loading but plasticizes copovidone above a critical APAP loading.
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Figure 8. Tablet tensile strength (n ¼ 3) of APAP-copovidone ASDs containing 0%, 5%, and 15% APAP. Powders were equilibrated at 32% RH (a) as a function of particle size at 100 MPa compaction pressure; (b) as a function of tablet porosity for the 75-125 mm fraction. Lines were obtained by exponential fitting.
The abrupt reduction in H at 40% APAP at 32% RH (Fig. 5b) corresponds to the state when the onset Tg is below room temperature (Fig. 5a). At this composition, significant softening of the ASD is expected because it has transitioned from a glassy state to a rubbery state. To further test the relationship between onset Tg and softening, ASD films equilibrated at 57% RH were examined. At the same APAP loading, the higher water content at 57% RH further reduced the Tg of the ASDs by about 5 C-7 C (Figs. 5 and 6a). At 57% RH, the Tg of ASD is close to room temperature at 20% APAP loading and drops below room temperature at 30% APAP loading (Fig. 6a). Corresponding to the state when the onset Tg is below room temperature, H significantly decreases when APAP loading increases from 20% to 30% (Fig. 6b). In fact, at 40% APAP loading, the film is too soft to trigger the nanoindenter for data collection. Data at both 32% and 57% RHs support that the softening of ASD is correlated to its transition to a rubbery state. At an identical APAP loading, both Tg and H are always lower at a higher RH (Figs. 4-7). This observation supports the role of water as a plasticizer and is corroborated by the observed effect of RH on film cracking behavior, which depends not only on APAP content but also environment RH. For example, a crack-free film is obtained when copovidone methanol solution is air dried at 40% RH. However, when the same film is equilibrated at 30% RH or lower, visible and audible cracking takes place. This observation indicates that copovidone is brittle at 30% RH (~4.3% water). However, the amount of water (6.3%) at 40% RH sufficiently plasticizes copovidone film to avoid cracking at room temperature. The sensitivity of H to RH variations in the range of 11%-57% (Figs. 6 and 7) highlights the need to control RH to avoid compromising the robustness of manufacturing process and consistency in the quality of tablet products containing an ASD. At each of the 3 levels of APAP loading, the tablet tensile strength decreased with increasing particle size (Fig. 8a). This is expected because larger particles have smaller surface area available for interparticulate bonding within a tablet. In addition to the particle size effect, a change in the intrinsic mechanical properties of ASD is also expected to influence bulk powder compaction behavior. Harder particles are more resistant to permanent plastic deformation under pressure,27,28 which negatively impacts tabletability of ASD powders by reducing the bonding area developed during compression. In fact, the tensile strength of tablets compressed at 100 MPa decreased significantly when 5% APAP was added to copovidone (Fig. 8a). Although the use of 15% APAP leads to a further reduction in tablet tensile strength, the reduction is minor in comparison to that of adding 5% APAP
(Fig. 8a). In any case, tablet tensile strength of ASD is deteriorated by the addition of APAP when the particle size effect is excluded. Tablet tensile strength decreased exponentially with increasing tablet porosity, consistent with the Ryshkewitch-Duckworth relationship29 (Fig. 8b). At a given porosity, including zero porosity, tablet tensile strength decreased with increasing APAP loading. Thus, the bonding strength between ASD particles is lower at a higher APAP loading between 0% and 15%. Regardless of the exact mechanism by which APAP incorporation reduced hardness, early access to this information would be extremely helpful to formulation scientists for designing robust ASD tablet formulations and manufacturing processes because mechanical properties of ASD are expected to play an important role in the tableting behaviors of formulations. For an ASD with deficiencies in mechanical properties, it is critical to choose suitable excipients during the formulation development to overcome such a challenge. Conclusions The mechanical properties of APAP-copovidone ASDs are sensitive to both moisture content and APAP loading. The incorporation of APAP initially hardens ASD through the process of filling the interstitial space. However, APAP also depresses Tg of ASD. ASD is softened when a sufficient amount of APAP depresses the Tg to below room temperature. Higher moisture content leads to both lower Tg and softer ASD at the same APAP loading. A clear understanding of the complex effect of APAP requires the considerations of both mechanical and thermal properties. We suggest that the mechanical properties, instead of Tg, should be used to classify plasticization/antiplasticization effects by a small molecule. We have also demonstrated that hardening of ASD by APAP impacts the tableting performance of ASD powders. Acknowledgments We thank Dr. Sathyanarayana R. Perumalla for technical support in characterizing solid state properties of ASD samples. This work was supported by a grant from AbbVie. References 1. Takagi T, Ramachandran C, Bermejo M, Yamashita S, Yu LX, Amidon GL. A provisional biopharmaceutical classification of the top 200 oral drug
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