Article pubs.acs.org/crystal
Rapid Assessment of the Physical Stability of Amorphous Solid Dispersions Pinal Mistry, Kweku K. Amponsah-Efah, and Raj Suryanarayanan* Department of Pharmaceutics, University of Minnesota, Minneapolis, Minnesota 55455, United States S Supporting Information *
ABSTRACT: Amorphous solid dispersions (ASDs) can potentially increase the apparent solubility and thereby the oral bioavailability of poorly soluble compounds. However, their physical instability, i.e., potential to crystallize, is a major concern. Our objective was to explore methods for rapid assessment of the physical stability of ASDs. Ketoconazole ASDs were prepared with each of the three polymers, poly(acrylic acid) (PAA), poly(2-hydroxyethyl methacrylate) (PHEMA), and polyvinylpyrrolidone (PVP). The physical stability of these ASDs was evaluated after exposure to 90% RH (25 °C) in an automated water sorption analyzer. The onset time for ketoconazole crystallization, induced by water sorption, was rank ordered as PAA > PHEMA > PVP. Additionally, the ability of the polymers to inhibit crystallization on contact with aqueous medium was studied by powder X-ray diffractometry using synchrotron radiation. In this case, the rank ordering was PAA ∼ PHEMA > PVP. To check the validity of our approach, the long-term stability of ketoconazole in ASDs was evaluated in the glassy state, both at 25 and at 40 °C, and was rank ordered as PAA > PHEMA > PVP. Crystallization, accelerated by water vapor sorption, can serve as an effective preliminary screening tool to rapidly evaluate and rank order the physical stability of ASDs.
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INTRODUCTION Amorphous solid dispersions (ASDs) are molecular mixtures of drug and polymer that can potentially offer pronounced solubility enhancement of drugs.1,2 The associated physical instability of this high-energy metastable form is a concern, because of the potential for the amorphous drug to revert to its crystalline form. Such a transition can negate the solubility and consequently the bioavailability advantage brought about by the amorphous form. For successful development of poorly soluble drugs as ASDs for oral administration, it is imperative that drug crystallization is prevented during both product manufacture and storage. Consequently, the physical stability of ASDs is taken into consideration during formulation development and optimization. The crystallization propensity of amorphous compounds was evaluated and categorized using differential scanning calorimetry (DSC).3 Ketoconazole, our model compound, in light of its low crystallization propensity, was categorized as a class III compound. We observed KTZ crystallization in ∼10 h following storage at 60 °C (Tg + 15).4 However, when stored at 25 °C (Tg − 20), the first evidence of crystallization was observed in a week. Therefore, for compounds such as ketoconazole which crystallize relatively slowly, assessment of physical stability can be time-consuming. In the case of ASDs, where often high polymer concentrations are used, the crystallization is further delayed, making it challenging to study the physical stability in reasonable time scales. It is practically very useful to develop methods to accelerate drug © XXXX American Chemical Society
crystallization with the goal of predicting long-term stability from short-term accelerated studies. X-ray diffractometry, differential scanning calorimetry, polarized light microscopy, atomic force microscopy, and dielectric and infrared spectroscopy have been utilized for rank ordering ASDs based on their stability.5−10 The structural diversity in ASDs has been probed using several techniques including solid-state NMR, differential scanning calorimetry, and scattering (both wide and small angle X-rays) techiques.11−13 In our previous studies, KTZ ASDs were prepared with each of these polymers: poly(acrylic acid) (PAA), poly(2hydroxyethyl methacrylate) (PHEMA), and polyvinylpyrrolidone (PVP). The strengths of interaction of each of these polymers with KTZ were very different. PAA exhibits ionic as well as strong H-bonding interactions with KTZ.7 PHEMA and PVP, respectively, reveal H-bonding and dipole−dipole interactions with KTZ. The stronger drug−polymer interaction translated to slower molecular mobility (longer relaxation time) as well as slower crystallization. Using a prediction model based on molecular mobility, the crystallization times in ASDs were estimated.4 While all of these investigations were carried out in the supercooled state, the stability of these systems in the glassy state is of immense practical interest. Received: December 29, 2016 Revised: March 12, 2017
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brane.21 As discussed earlier, since KTZ crystallizes slowly, it is an excellent candidate to test our stability screening approach. KTZ ASDs were prepared with PAA, PHEMA, and PVP. The water uptake behavior of the glassy ASDs was studied using an automated water sorption apparatus. Synchrotron radiation was used to evaluate the crystallization tendency of the glassy ASDs when wetted with buffer (pH 7.4; phosphate). Finally, the ASDs in the glassy state were subjected to long-term (>2 years) physical stability evaluation, again using synchrotron radiation to detect KTZ crystallization. It was therefore possible to evaluate the validity of the short-term accelerated studies with real-time long-term studies. Overall, our goal was to develop a rapid screening method to assess the physical stability of ASDs which will enable the rank-ordering of their long-term stability.
In the glassy state, predicting crystallization times is very challenging due to the low molecular mobility of the system. Water can be sorbed by amorphous dispersions, during the manufacturing process as well as product storage. The consequent plasticization can result in a dramatic decrease in physical stability of the drug and accelerate drug crystallization.14 Water sorption can also lead to phase separation and bring about physical instability.15 Recently, water sorption was proposed as an accelerated stability testing approach, to predict crystallization times in ASDs. 16 Greco et al. studied crystallization of ASDs at elevated temperature and water vapor pressure for a short-term period (3 months) to predict the long-term stability. By using water as a plasticizer, felodipine crystallization was accelerated in ASDs.17 The extent of coupling between molecular mobility and crystallization times in felodipine-PVP ASD remained unaffected at low water content (98%) was obtained from Laborate Pharmaceuticals (Haryana, India) and used without further purification. Poly(acrylic acid) (PAA; Mw ∼ 1800) was purchased from Sigma-Aldrich (Missouri, USA) and PVP (K12 grade, Mw ∼ 2000−3000) was a gift from BASF (New Jersey, USA). PHEMA, custom synthesized to Mw ∼ 3700, was purchased from Polymer Source (Quebec, Canada). The polymers were dried at 110 °C for 1 h and stored in desiccators containing anhydrous calcium sulfate until use. Preparation of Amorphous Systems. The preparation method was detailed earlier.7 Briefly, amorphous KTZ was obtained by heating crystalline KTZ to 160 °C (∼10 °C above its melting point) and quench-cooling in liquid nitrogen. ASDs were prepared by dissolving the drug and polymer in methanol, followed by solvent evaporation and melt-quenching. ASDs were prepared with either 4% or 10% w/w polymer. Water Sorption Analysis. The water sorption profiles of ASDs, physical mixtures of amorphous drug and polymer, as well as the pure components (polymer, amorphous drug, and crystalline drug) were obtained using an automated vapor sorption analyzer (DVS-1000 Advantage, Surface Measurement Systems, Middlesex, UK). Approximately 15 mg of powder was placed in a quartz sample pan, and equilibrated at 0% RH (25 °C) for 1 h under a nitrogen flow rate of 200 mL/min. The RH was then increased to 90% and held for up to 48 h. The first time point when a weight loss was observed (dm/dt reaches a negative value) was taken as the crystallization onset time. At least three measurements (n ≥ 3) were performed, using a fresh sample for each run. Synchrotron X-ray Diffractometry (XRD). Sample Preparation for Wetting Experiment. Approximately 20 mg of the powder sample was accurately weighed in a DSC pan (Tzero, TA Instruments, DE) and 25 μL of phosphate buffer (pH 7.4; 0.2 M concentration) was added to uniformly wet the sample. The DSC pan was hermetically sealed and mounted on a custom-made aluminum sample holder. The measurements were performed in duplicate using fresh amorphous sample for each run. Evaluation of the Physical Stability of GlassSample Preparation. The stability of amorphous drug as well as the ASDs in the glassy state were evaluated by storing powder samples in ovens (UFE 500 Memmert, Schwabach, Germany) at four temperatures, in the range of 25 to 40 °C. At the desired time periods, the powders were hermetically sealed in DSC pans (Tzero, TA Instruments, DE) in a glovebox (RH < 5%; room temperature). The pans were mounted on the sample holder as described earlier. Experimental Details. The samples were exposed to synchrotron radiation (0.72808 Å; 17-BM-Sector; Argonne National Laboratory, IL) in transmission mode with a sample-to-detector distance of 900 mm. The pan was oscillated (±1 mm from the center) along the horizontal axis using a stepper motor. The results from 30 scans were averaged, with an exposure time of 1 s per scan. The calibration was performed using Al2O3 standard (SRM-647a, NIST). An amorphous silicon flat panel detector (XRD 1621, PerkinElmer, CA) was used to B
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Figure 1. (a) Water sorption behavior of KTZ and KTZ ASDs when stored at 90% RH and 25 °C. The polymer concentration in ASDs was 10% w/ w. The onset time for weight loss is pointed out. (b) Derivative of curves from (a) for amorphous systems. The derivative plot was smoothed using a commercially available software (Sigmaplot Systat Software, CA). (c) The inset in (a) is magnified to show differences in water sorption kinetics in the initial time period. obtain the diffraction patterns in two-dimensional (2D) mode. The 2D data was integrated to obtain the one-dimensional (1D) pattern using GSAS-II software.22 In order to enable comparison with the laboratory X-ray data, the 2θ values were converted for Cu Kα radiation using a commercially available software (JADE 2010, Material Data, Inc., CA). Differential Scanning Calorimetry (DSC). A differential scanning calorimeter (TA Instruments Q2000, DE) was used for thermal analysis. The instrument was equipped with a refrigerated cooling accessory (RCS 90, TA Instruments, DE) and calibrated with indium. Approximately 5−10 mg of sample was hermetically sealed in an aluminum pan. All measurements were performed at a heating rate of 10 °C/min under nitrogen purge (50 mL/min). Each sample was heated to about 10 °C above Tg, held for 5 min, and then cooled to −50 °C, followed by heating above the melting point of drug. The Tg value was determined at the midpoint of the transition, and the enthalpy of melting (ΔHm) was normalized for KTZ content.
expected, only a small amount of water was sorbed by crystalline KTZ (weight gain PVP. The rate and extent of water uptake by ASDs was investigated in detail (Figure 1c). The water sorption occurred most rapidly in PVP ASDs. For example, in 40 min, the water uptake by PAA, PHEMA, and PVP ASDs were ∼5%, 7%, and 9%, respectively. We had previously pointed out that interaction of KTZ with PAA, or with PHEMA, was much stronger than with PVP. PAA formed ionic as well as strong Hbonding interactions with KTZ.7 PHEMA and PVP respectively showed H-bonding and dipole−dipole interactions with KTZ. As the strength of the drug−polymer interaction increased, there was a reduction in the rate and extent of water uptake. Thus, the more effective crystallization inhibition by PAA and PHEMA in the presence of water can be attributed to the strong drug−polymer interactions and the consequent reduction in water uptake. Aso et al. determined the spin− lattice relaxation times in sucrose and sucrose−PVP dispersions. Following water sorption, the decrease in relaxation time (reflecting an increase in molecular mobility) was more pronounced in neat sucrose than in the dispersions. The strong H-bonding between sucrose and PVP was suggested to be responsible for the lower molecular mobility in the presence of sorbed water.23 At this point, it is instructive to consider the water sorption behavior of the individual polymers (Figure 2). PVP was
Figure 2. Water uptake kinetics of polymers at 90% RH and 25 °C.
hygroscopic and sorbed >55% water in 400 min while the water content in PAA and PHEMA was ∼40% and 27%, respectively. Interestingly, PAA sorbed more water than PHEMA, although the amount of water sorbed by PAA ASDs was less than that by PHEMA ASDs (Figure 1). This can be explained by the strong drug−polymer interaction limiting the water uptake. The amount of water sorbed by indapamide-PVP ASD was less than that by physical mixtures of the same composition, an effect attributed to strong−drug polymer interactions.24 Recently, in KTZ ASDs, HPMCAS was shown to provide more effective crystallization inhibition in the presence of water as compared to PVP-VA.25 The strong interaction between KTZ and HPMCAS was believed to make ASDs more hydrophobic and restrict the water uptake. Spectroscopy revealed that the sorbed water disrupted the weaker interactions between KTZ and PVP-VA, but did not affect the strong H-bonding between KTZ and HPMCAS. However, this behavior is not universal. In dispersions of only hydrophilic components, such as sucroseD
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water by the polymer. The water released following crystallization may be sorbed by the polymer, thereby interfering with the detection of crystallization. Synchrotron XRD Analysis. Since XRD provides direct evidence of crystallization, it can be used as a complementary screening method to rank order dispersions. A substantial enhancement in sensitivity is achieved by using the powerful, high-flux of synchrotron radiation. As a result, it is possible to detect low levels of crystallization in ASDs.36 Each ASD was wetted with phosphate buffer (0.2 M; pH 7.4) and subjected to synchrotron XRD as a function of time. In PAA and PHEMA ASDs, the first evidence of crystallization was observed following storage for 95 min (Figure 3). In contrast, the
Figure 4. XRD patterns of amorphous KTZ and KTZ−polymer physical mixtures, 45 and 95 min after wetting with phosphate buffer. Some characteristic peaks of KTZ (*) and the sample holder (#) are pointed out.
interaction with KTZ. In contrast, our water sorption studies showed most pronounced crystallization inhibition by PAA (Figure 1a). On contact of water with ASDs, multiple confounding factors affect the physical stability of ASDs and may contribute toward such differences. PAA is freely soluble in water and can therefore facilitate the generation of a supersaturated drug solution. Thermodynamically, such high supersaturation favors crystallization. The solid-state stability enhancement offered by PAA, may be offset by its high aqueous solubility. PHEMA, being a water-insoluble polymer, can likely restrict the rate and extent of supersaturation. This may explain the virtually similar physical stability observed in PHEMA and PAA ASDs. Previously, in indomethacin ASDs, water-soluble polymers such as HPMCAS and PVP rapidly dissolved and generated highly supersaturated solutions, triggering rapid nucleation and crystallization. In comparison, the waterinsoluble PHEMA hydrogel provided a diffusion-controlled dissolution of drug that prevented the sudden surge of supersaturation and consequent drug crystallization.37,38 Although the wetting experiment is a rapid complementary technique to detect crystallization in ASDs, it lacked the sensitivity to distinguish between the stabilities of the PHEMA and PVP dispersions. In comparison, the rank order of physical stability of ASDs (PAA > PHEMA > PVP) obtained by the water sorption analysis was the same as that observed in our earlier studies under “dry” conditions in the supercooled state.4 While we had already demonstrated the use of molecular mobility to estimate the crystallization times in ASDs and rank order the ASDs, all of those investigations were carried out in the supercooled state. Practically, it is of interest to study the physical stability in the glassy state, where the ASDs are likely to be stored during the shelf life of the drug product. Thus, the long-term stability of ASDs in glassy state was studied. Long-Term Storage Stability of KTZ ASDs. In order to check the validity of our approach, ASDs with polymer concentrations of 4%, 8%, and 20% w/w were prepared and stored at either 25 or 40 °C in glass vials, at a relative humidity PVP. Our results from wetting experiments followed by synchrotron XRD confirm that the dispersions with strong drug− polymer interactions (PAA and PHEMA ASDs) showed higher stability than PVP ASDs. If drug−polymer interactions were truly responsible for the observed enhancement in physical stability, such crystallization inhibitory effects are not expected in physical mixtures of amorphous drug and polymer. Indeed, negligible inhibitory effect was observed in physical mixtures as shown in Figure 4. The crystallization onset times in physical mixtures were virtually similar to that of amorphous KTZ (∼45 min). Since the crystallization onset times were consistently longer in ASDs, drug-polymer interactions appear to be responsible for inhibiting drug crystallization in the presence of water. Similar observations were made in amorphous sucrose-PVP systems, where effective crystallization inhibition in the presence of water was observed in dispersions when compared with the corresponding physical mixtures.26,27 While poor crystallization inhibition by PVP was confirmed by synchrotron XRD analysis, we could not discriminate between PAA and PHEMA, which differed in their strength of E
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crystallized within 3 days following storage at 40 °C (Supporting Information, Figure S1). In contrast, no crystallization was observed up to 24 days in both PAA and PVP ASDs with either 8% or 20% polymer. Considering the long crystallization times in ASDs, crystallization studies were discontinued in ASDs with 8% and 20% polymer concentrations. Only dispersions with 4% polymer were evaluated further. Even at this low polymer concentration, the differences in their ability to inhibit drug crystallization was readily evident (Figure 5). Freshly prepared amorphous KTZ as well as the
expect longer crystallization times in physical mixtures as compared to amorphous KTZ. Our results from XRD studies show that this is clearly not the case (crystallization times in physical mixtures and amorphous KTZ were virtually similar). The physical stability of ASDs was also studied at room temperature (25 °C) and followed the same rank order. PAA effectively inhibited drug crystallization from ASDs for >2 years (Figure 6). In comparison, in PHEMA and PVP ASDs drug
Figure 6. XRD patterns of KTZ ASDs (4% w/w polymer) stored at 25 °C for different time periods. The XRD pattern of crystalline KTZ (“as is”) is provided for reference. Some characteristic peaks of KTZ (*) and the sample holder (#) are pointed out.
Figure 5. Two-dimensional XRD patterns of amorphous KTZ and ASDs (4% w/w polymer) following storage at 40 °C. The XRD pattern of crystalline KTZ (“as is”) is included as a reference. Selected diffraction rings, due to KTZ crystallization, are pointed out.
crystallization was evident in ∼8 and 4 months, respectively. Considering the low polymer content (4% w/w) in ASDs, the substantial increase in physical stability observed in PAA dispersions may be surprising. Such effective crystallization inhibition of KTZ by PAA can be attributed to considerable reduction in molecular mobility through drug−polymer interactions. In our previous work, we established that stronger drug−polymer interactions provided a disproportionate decrease in molecular mobility which translated to a significant increase in physical stability.7,39 Polymer−polymer interactions through ionic and H-bonding, resulted in orders of magnitude increase in viscosity.40 Such an effect of intermolecular interactions on viscosity is much more dramatic as the temperature is reduced. The increase in viscosity will translate to a corresponding decrease in mobility. The formation of “ionic clusters” or “temporary cross-links” has been suggested as the underlying mechanism.41−43 Such clustering/crosslinking can significantly increase the viscosity (i.e., decrease the molecular mobility) and may explain years of stability in ASDs with strong drug−polymer interactions. Based on this understanding, in ASDs with strong drug−polymer interactions, a reduction in storage temperature is expected to provide a disproportionate increase in physical stability. We wanted to show that the reduced molecular mobility was indeed an explanation for the unusually long crystallization times and that KTZ was still capable of crystallizing out from PAA ASDs, if there was a sufficient increase in mobility. To test this hypothesis, the samples were stored at 25 °C for 118 weeks and then subjected to DSC and isothermal XRD. This enabled us to compare the crystallization behaviors of the fresh and
ASDs were confirmed to be amorphous. Crystallization of amorphous KTZ was quite pronounced following 24 days of storage at 40 °C. At this storage time, all the dispersions remained amorphous. Crystallization from PVP and PHEMA ASDs was observed after 40 and 308 days, respectively. In comparison, PAA was most effective at inhibiting drug crystallization and remained amorphous for >1 year after storage at 40 °C (Supporting Information, Figure S2). Based on the long-term crystallization studies in the glassy state [40 °C, i.e., ∼(Tg − 5)], the physical stability of ASDs was rank ordered as PAA > PHEMA > PVP. Our results revealed that in the glassy state, PVP was modestly effective in inhibiting KTZ crystallization (Figure 5). This was in contrast to its ineffectiveness in the supercooled state wherein the PVP ASD and amorphous KTZ exhibited virtually similar crystallization times (and molecular mobility).4 Since the glassy state is characterized by low molecular mobility, we believe that even weak dipole−dipole interactions between drug and polymer may play a significant role in improving physical stability. To explore this further, the molecular mobility of ASDs in the glassy state is currently under investigation. Although one can argue that the physical barrier to crystallization due to dilution by the polymer may be the contributing factor, at a polymer concentration of 4% w/w, this effect is not expected to be pronounced. Additionally, if the dilution effect contributed to physical stability, we can also F
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such cases, this approach may incorrectly suggest that the ASDs are physically stable (“false positive”). Nevertheless, this is a useful approach for rapid screening of polymers and assessment of the physical stability of ASDs. Studies aimed at understanding the interaction between water, API, and polymers at the molecular level would provide useful insights into the stabilization mechanism of polymers.
stored samples. The DSC heating curve of the freshly prepared ASDs showed a Tg ∼ 47 °C, followed by crystallization at ∼138 °C and melting at ∼148 °C (Figure 7). These results were in
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b01901. Figure showing XRD patterns of amorphous systems following storage at 40 °C up to 24 days and figure showing XRD patterns of KTZ-PAA ASDs following storage at 40 °C for >1 year (PDF)
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AUTHOR INFORMATION
Corresponding Author
Figure 7. DSC heating curves of KTZ-PAA ASDs: (a) freshly prepared, and (b) following storage at 25 °C for 118 weeks.
*E-mail:
[email protected]. ORCID
Raj Suryanarayanan: 0000-0002-6322-0575
excellent agreement with the previously reported values.7 Following storage at 25 °C (i.e., “annealing”), a slightly lower Tg value (42.4 °C) and considerably lower crystallization temperature (∼130 °C) were observed. Additionally, the enthalpy of melting of the stored sample was much higher than that of the freshly prepared samples. These results suggest that nucleation occurred during storage at 25 °C (for >2 years). Nonetheless, there was no evidence of crystallization even using highly sensitive synchrotron radiation. A similar effect of “annealing” has been observed in trehalose, where the crystallization onset temperature decreased as a function of annealing time.44 In light of the slow crystallization observed in glassy ASDs, the need for an accelerated stability study is clearly evident. The ability to assess the long-term crystallization risk and thereby rank order the ASDs for their physical stability is highly valuable during formulation development and optimization. Our two-step stability assessment approach provides rapid evaluation of physical stability in ASDs within hours, using water as a “crystallization accelerator”. By using both water sorption and synchrotron XRD following wetting of ASDs, we have assessed the physical stability of ASDs to rank order the dispersions. In our studies, water sorption analysis provided reliable prediction of long-term stability of glassy ASDs under “dry” conditions. Using synchrotron XRD, we have confirmed the role of strong drug−polymer interactions in enhancement of stability in the presence of water. During early formulation design, our suggested approach can potentially help in rank ordering ASDs and provide a quick, preliminary evaluation of the long-term stability.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The project was partially funded by the William and Mildred Peters endowment fund and the Centre for Pharmaceutical Processing and Research. Parts of this work were carried out in the Characterization Facility, University of Minnesota, a member of the NSF-funded Materials Research Facilities Network (www.mrfn.org). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. We thank Dr. Gregory Halder and Dr. Wenqian Xu at Argonne National Laboratory for their help during the synchrotron data collection. Dr. Seema Thakral and Karlis Berziņ ̅ ̅ s ̌ are thanked for their useful comments.
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CONCLUSIONS We have evaluated two approaches to rapidly assess the physical stability of ASDs. The rank order for physical stability based on short-term water sorption studies and long-term realtime storage in glassy state were identical, i.e., PAA > PHEMA > PVP. Thus, water sorption analysis was a reliable predictor of long-term physical stability of ASDs under “dry” conditions. One of the major limitations of the proposed method is that, in some instances, crystallization may not reveal a weight loss. In G
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DOI: 10.1021/acs.cgd.6b01901 Cryst. Growth Des. XXXX, XXX, XXX−XXX
