Article Cite This: Cryst. Growth Des. XXXX, XXX, XXX−XXX
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Compression-Induced Crystallization in SucrosePolyvinylpyrrolidone Amorphous Solid Dispersions †,‡ Karlis and Raj Suryanarayanan*,‡ ̅ Berziņ ̅ š †
Latvian Institute of Organic Synthesis, Aizkraukles iela 21, LV-1006 Riga, Latvia Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 308 Harvard Street S.E., Minneapolis, Minnesota 55455, United States
‡
S Supporting Information *
ABSTRACT: Tablets of amorphous sucrose and sucrosepolyvinylpyrrolidone (PVP) amorphous solid dispersions were compressed at 25, 75, or 150 MPa at dwell times ranging from 5 to 900 s. Compression-induced physical destabilization was evident from differential scanning calorimetry. Crystallization kinetics was monitored using a laboratory source X-ray diffractometer, while crystallization was detected using highly sensitive synchrotron radiation. At the highest compression pressure, sucrose crystallization was evident immediately after compression. However, the addition of PVP, even at a low concentration of 1% w/w, inhibited crystallization. Furthermore, nucleation itself was completely prevented at higher PVP concentrations (≥15% w/w) under a compression pressure of practical interest (150 MPa with 5 s dwell time). However, an increase in dwell time (e.g., to 60 s) facilitated nucleation, and there was an increase in nucleation density as a function of dwell time. Both polymer content and sample history were pivotal factors limiting compression-induced crystallization in plasticized amorphous systems. Generally, plasticization was found to amplify compression-induced destabilization. PVP, in a concentration dependent manner, attenuated this effect.
1. INTRODUCTION Nearly 90% of new chemical entities (drug candidates under development) are poorly water-soluble.1 This can potentially translate to poor bioavailability following oral administration. Amorphization is one approach to enhance the aqueous solubility of compounds.2 However, physicochemical instability of amorphous drugs, i.e., their potential to crystallize, warrants careful consideration.3 The manufacture of solid oral dosage forms (for example, tablets) entails a number of processing steps. Several of these steps can destabilize amorphous phases. For example, milling, a process for particle size reduction, is known to cause crystallization.4 Earlier work from our laboratory had shown that compression can cause crystallization of amorphous indomethacin.5 Surprisingly, even a very low compression pressure of 10 MPa caused crystallization in practical time scales. Compression-induced destabilization has also been shown in sucrose and in celecoxib.6,7 Mechanistically, the densification of the amorphous phase brought about by compression, is believed to be responsible for crystallization. The process reduces the density difference between the amorphous and crystalline states. It is postulated that each amorphous material has an upper density limit, beyond which external pressure induces strain and causes crystallization.8 Our discussion so far was restricted to the drug substance. Practically, it will be unusual to formulate an amorphous compound directly. Instead, a molecular mixture of the drug is © XXXX American Chemical Society
prepared, usually with a polymer. The resulting amorphous solid dispersions (ASDs), often, but not always, confer the desired physical stability. Furthermore, solid dispersion technology has been successfully applied to develop formulations with a high drug loading.9 Singh et al. have recently shown that compression can induce changes in the “architecture” of itraconazole-Soluplus ASDs.10 Compression of the ASD, both under pharmaceutically relevant conditions and under extreme pressures and dwell times, revealed phase separation. Interestingly, the influence of compression on the physical stability of ASDs has not received adequate attention. This issue is particularly relevant for amorphous drugs which are sensitive to compression. It is instructive to recognize that product storage and crystallization may occur in comparable time scales. The process of crystallization consists of nucleation followed by crystal growth. It can be challenging to detect compressioninduced nucleation. Crystallization may become evident only after there is adequate growth. Until then, the product for all intents and purposes is amorphous, and there will be no evidence of any “potential danger” due to crystallization. In such systems, any approach to “accelerate crystallization” can be Received: September 14, 2017 Revised: December 4, 2017 Published: December 6, 2017 A
DOI: 10.1021/acs.cgd.7b01305 Cryst. Growth Des. XXXX, XXX, XXX−XXX
Crystal Growth & Design
Article
The sucrose-PVP ASD with 2.5% polymer concentration was additionally compressed at 25 and 75 MPa pressure (dwell time 5 s), and these tablets were 3.5 and 3.2 mm thick, respectively. The powder samples and the compression assembly were handled in a controlled environment (RH < 5%; RT). 2.5. Water Sorption. Sucrose and sucrose-PVP ASDs (∼300 mg) were stored in chambers maintained at room temperature (∼25 °C) under controlled relative humidity (RH). The desired RH was achieved using saturated salt solutions as well as sulfuric acid solutions of different concentrations. The salts used (only the anhydrous form is shown here) and the corresponding RH values were LiCl (11%), CH3CO2K (22.5%), MgCl2 (32%), and K2CO3 (43%).16 The sulfuric acid solutions, 65% w/v and 55% w/v were used to obtain RH values of 17 and 27%, respectively.17 The composition was confirmed from density measurement (1.55 and 1.42 g/mL for the 65 and 55% solutions, respectively). The water uptake by the amorphous phases was monitored gravimetrically, and the final water content was confirmed by KFT. These samples were compressed into tablets under ambient conditions (∼25 C; ∼20% RH). 2.6. Differential Scanning Calorimetry (DSC). A differential scanning calorimeter (Q2000, TA Instruments, Delaware, USA) equipped with a refrigerated cooling accessory was used. The instrument was calibrated with tin and indium. Approximately 8 mg of sample was hermetically sealed in an aluminum pan inside a glovebox (RH < 5%) or under ambient conditions (RH ≈ 20%; for plasticized samples), heated at 10 °C/min, from 0 to 200 °C under nitrogen purge (50 mL/min). 2.7. Fourier Transform Infrared Spectroscopy (FTIR). The attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) spectra were obtained at room temperature on a Bruker Vertex 70 spectrometer (Bruker, Massachusetts, USA) equipped with a platinum ATR accessory. The spectra were recorded (16 scans) from 600 to 4000 cm−1 at a 4 cm−1 spectral resolution. 2.8. X-ray Powder Diffractometry (XRD). An X-ray diffractometer (D8 ADVANCE, Bruker AXS, Wisconsin, USA) equipped with variable-temperature stage (TTK 450, Anton Paar, GrazStraβgang, Austria) and a Si strip one-dimensional detector (LynxEye, Bruker AXS, Wisconsin, USA) was used. The measurements were performed at 95 °C, under nitrogen purge, using Cu Kα radiation (1.5406 Å, 40 kV, and 40 mA), and data were collected over the range of 5−35° 2θ with a step size of 0.02° and dwell time of 0.1 s. The degree of crystallinity, at each time point, was calculated using eq 1 and can be expressed as % crystallinity, if the total diffracted intensity (crystalline + amorphous) remains approximately constant throughout the experiment. This was confirmed (details in Supporting Information, Figure S1).18
immensely helpful and enable identification of potentially unstable systems. In order to comprehensively understand the effect of compression on amorphous phase destabilization, sucrose was selected as a model compound. The effect of temperature and water vapor pressure on the physical stability of sucrose is wellknown and understood.11,12 As stated earlier, sucrose is known to be sensitive to compression. Imamura et al. have shown that the crystallization behavior of sucrose was altered following compression at different pressures (74−667 MPa), and the formation of nuclei and subsequent crystal growth were accelerated by compression.6 Polyvinylpyrrolidone (PVP) was the model polymer and amorphous solid sucrose-PVP dispersions were prepared. Since sucrose hydrogen bonds with PVP, even a low PVP concentration can effectively inhibit crystallization. Furthermore, sucrose-PVP systems have also been the subject of numerous studies and have been comprehensively characterized.13−15 Therefore, it was possible to systematically study the effect of numerous factors of interest, specifically plasticization, polymer concentration, compression pressure, and dwell time on its crystallization behavior. Our goal was to develop mechanistic insights into compression-induced destabilization (i.e., crystallization) in amorphous dispersions. We hypothesize that (i) Polymers, in a concentration dependent manner, can inhibit the crystallization propensity of drugs sensitive to compression. (ii) In glassy systems, as the Tg approaches the compression temperature, crystallization is facilitated (accelerated). The hypotheses were tested by evaluating the crystallization behavior of sucrose-PVP dispersions (up to 75% w/w PVP), the Tg of which ranged from 70 to 112 °C. Selected systems were plasticized (Tg range of 35 to 72 °C) and compressed, and the crystallization behavior was evaluated. The crystallization was substantially accelerated in the plasticized system, an effect possibly attributable to compression-induced nucleation.
2. EXPERIMENTAL SECTION 2.1. Materials. Sucrose (α-D-glucopyranosyl β-D-fructofuranoside, C12H22O11) and PVP-K30 (Mw ≈ 40000) were obtained from MP Biomedicals (Ohio, USA) and BASF (New Jersey, USA), respectively. All the solvents and other chemicals were of analytical grade. 2.2. Preparation of Spray-Dried Amorphous Sucrose and Sucrose-PVP ASDs. Spray-drying was carried out in a mini spraydryer (model B-191, Buchi, Switzerland). Sucrose and sucrose-PVP physical mixtures with different polymer loadings (1.0, 2.5, 4.0, 5.0, 7.5, 10.0, 15.0, 30.0, 50.0, and 75.0% w/w) were dissolved (10% w/v) in water and introduced at a feed rate of 2.6 mL/min. The inlet temperature was 95−120 °C, and the outlet temperature range was 60−88 °C. Spray-dried samples had initial water content of ∼1.2− 2.3% w/w. These were subsequently dried at 40 °C and 0% RH for 24 h (72 h for systems with a polymer concentration ≥30%). The final water content in amorphous sucrose was ≤0.5% w/w and ≤1.1% w/w in the ASDs. 2.3. Karl Fischer Titrimetry (KFT). The water content in the samples (∼30 mg) was determined by coulometric Karl Fischer titration (C20 Coulometric KF titrator, Mettler Toledo, Ohio, USA). 2.4. Tablet Preparation. Tablets (flat-faced plain, 8 mm diameter, 3 mm thick) were prepared by compressing amorphous sucrose or sucrose-PVP ASD powder (200 mg) using stainless steel die and punches, in a hydraulic press (Carver Model C Laboratory press, Wisconsin, USA). Unless otherwise stated, the compression pressure was 150 MPa and the dwell time was 5 s. The sucrose-PVP ASD (15% PVP) were also compressed at dwell times of 60, 120, 300, and 900 s.
%crystallinity =
intensity of crystalline peaks × 100 total diffracted intensity
(1)
A custom-built program (using Fortran 77; Tucson, AZ) was used to quantify crystallinity.19 The amorphous intensity contribution was based on the experimental XRD pattern of the amorphous “reference” materials (prepared as described above). The amorphous intensity was subtracted from the total pattern to yield the crystalline intensity contribution. The percent crystallinity was plotted as a function of time, and a characteristic crystallization time (tc) was defined as the time for 5% crystallization. 2.9. Synchrotron X-ray Diffractometry (SXRD). Selected samples were analyzed by SXRD, where ∼20−25 mg of powder material was filled in aluminum pans (used for DSC analysis, TA Instruments), crimped hermetically at room temperature inside a glovebox (RH < 5%), and placed in a specially fabricated holder.19 Experiments were performed in the transmission mode using synchrotron radiation in the 17-BM-B beamline at Argonne National Laboratory (Illinois, USA). A monochromatic X-ray beam (wavelength 0.72910 Å, circular beam with a diameter of 300 μm) and a twodimensional area detector (XRD-1621, PerkinElmer) were used. The sample to detector distance was set at 900 mm and the pan was oscillated (±1 mm from the center) along the horizontal axis using a B
DOI: 10.1021/acs.cgd.7b01305 Cryst. Growth Des. XXXX, XXX, XXX−XXX
Crystal Growth & Design
Article
stepper motor. The results from 30 scans were averaged, with an exposure time of 1 s per scan. A triple-bounce channel-cut Si single crystal monochromator with [111] faces polished was used, which limited the line broadening to its theoretical limit, i.e., the Darwin width. The flux of the incident X-ray was 8 × 1011 photons/s @ 17 keV. The calibration was performed using Al2O3 (SRM-647a, NIST). The two-dimensional (2D) data were integrated to yield onedimensional (1D) 2θ (deg) scans using the GSAS-II software.20 Comparison with laboratory X-ray data was enabled by converting the scans for the wavelength of Cu Kα radiation (1.5406 Å) using commercially available software (JADE 2010, Material data, Inc.).
In amorphous sucrose, glass transition (Tg) was observed at ∼72 °C (midpoint), followed by crystallization (exotherm) and melting (endotherm) at 117 and 187 °C, respectively. The reported Tg values of sucrose range from 48 to 78 °C.21 Both the preparation method and the water content will have a pronounced effect on the Tg. Our observed “high” value reflects the low water content in the sample (∼0.5%). The heat capacity change (ΔCp) at Tg of amorphous sucrose was 0.70 J/g °C, which again was in agreement with the reported values ranging from 0.55 J/g °C to 0.77 J/g °C (Table 1).21 The enthalpic recovery of sucrose, evident from the endotherm following the glass transition, reflects relaxation of the amorphous phase during preparation or storage or both. In the sucrose−PVP ASDs, progressive polymer addition first caused a decrease and then an increase in Tg compared to amorphous sucrose alone. Earlier studies had shown that PVP at low concentrations (10%), effectively inhibited nucleation as H
DOI: 10.1021/acs.cgd.7b01305 Cryst. Growth Des. XXXX, XXX, XXX−XXX
Crystal Growth & Design
Article
Figure 9. Plot of crystallization time (tc, time taken for 5.0% crystallization) versus Tg of the sample. The Tg refers to the glass transition temperature of the sample at its time of compression. This was modulated based on the amount of water sorbed by the sample. The crystallization time was obtained from isothermal XRD studies at 95 °C (n ≥ 3). Insets (a) and (b) provide clear representation of the data for amorphous sucrose and sucrose-PVP ASD (5% w/w) samples, respectively (the symbols for data points are enlarged for clarity). The lines are drawn to assist in visualizing the trends. Filled circles: compressed samples; open circles: uncompressed “as is” samples - control (i); unfilled squares: plasticized and dried samples - control (ii). The detailed sample history is provided in Scheme 1.
temperature became evident by DSC. Therefore, DSC appears to be a more sensitive indicator of processing-induced destabilization. This is a valuable attribute when crystallization is a very “slow” process and is observed long after product manufacture (for example, several months). In such instances, DSC has the potential to reveal destabilization immediately after product manufacture. However, there is a major limitation with DSC. Since the temperature of crystallization is substantially above the processing temperature (RT), the potential for changes in composition during the DSC run warrant consideration. While this is of unlikely concern for simple systems (such as under current investigation), it can be a serious limiting factor for complex, multicomponent systems as in actual pharmaceutical dosage forms.
well. When the system was plasticized and compressed, the destabilizing effect was much more pronounced (Figure 9). This effect could be substantially negated at a modest polymer concentration of 5%. Our work provides mechanistic insights, both into destabilization and the potential role of polymer, in circumventing the problem. The potential for compressioninduced nucleation can be negated, substantially if not completely, at a modest polymer concentration. Amorphous phases are characterized by a strong tendency to sorb water. The consequent plasticization, during manufacture or storage, can amplify the compression-induced destabilization. Again, the polymer in a concentration dependent manner, substantially diminished this effect. We believe that this is first report wherein the destabilization effects of compression and plasticization have been simultaneously investigated. The techniques of DSC and XRD provided complementary information enabling us to comprehensively characterize the system. DSC was an indirect technique in that it revealed the consequence of nucleation through a change in the temperature of crystallization. XRD, specifically the synchrotron source, directly revealed the formation of a crystalline phase. However, long before the presence of crystalline phase was revealed by XRD, a decrease in the temperature of crystallization
4. CONCLUSIONS The effect of compression on the physical stability of amorphous sucrose and sucrose-PVP ASDs was comprehensively studied. The combination of analytical techniques (particularly DSC and SXRD) provided mechanistic insights into the compression-induced destabilization in these amorphous phases. Interestingly, compression induced crystallization in amorphous sucrose under tableting conditions of practical I
DOI: 10.1021/acs.cgd.7b01305 Cryst. Growth Des. XXXX, XXX, XXX−XXX
Crystal Growth & Design
Article
(11) Yu, X.; Kappes, S. M.; Bello-Perez, L. a.; Schmidt, S. J. J. Food Sci. 2008, 73 (1), E25−E35. (12) Bhugra, C.; Rambhatla, S.; Bakri, A.; Duddu, S. P.; Miller, D. P.; Pikal, M. J.; Lechuga-Ballesteros, D. J. Pharm. Sci. 2007, 96 (5), 1258− 1269. (13) Shamblin, S. L.; Taylor, L. S.; Zografi, G. J. Pharm. Sci. 1998, 87 (6), 694−701. (14) Bhattacharya, S.; Suryanarayanan, R. Pharm. Res. 2011, 28 (9), 2191−2203. (15) Bhattacharya, S.; Bhardwaj, S. P.; Suryanarayanan, R. Pharm. Res. 2014, 31 (10), 2822−2828. (16) Greenspan, L. J. Res. Natl. Bur. Stand., Sect. A 1977, 81A (1), 89. (17) Wilson, R. J. Ind. Eng. Chem. 1921, 13 (4), 326−331. (18) Nunes, C.; Mahendrasingam, A.; Suryanarayanan, R. Pharm. Res. 2005, 22 (11), 1942−1953. (19) Mistry, P.; Suryanarayanan, R. Cryst. Growth Des. 2016, 16 (9), 5141−5149. (20) Toby, B. H.; Von Dreele, R. B. J. Appl. Crystallogr. 2013, 46 (2), 544−549. (21) Lappalainen, M.; Pitkanen, I.; Harjunen, P. Int. J. Pharm. 2006, 307 (2), 150−155. (22) Mistry, P.; Mohapatra, S.; Gopinath, T.; Vogt, F. G.; Suryanarayanan, R. Mol. Pharmaceutics 2015, 12, 3339−3350. (23) Zhang, J.; Zografi, G. J. Pharm. Sci. 2001, 90 (9), 1375−1385. (24) Trasi, N. S.; Byrn, S. R. AAPS PharmSciTech 2012, 13 (3), 772− 784. (25) Mehta, M.; Kothari, K.; Ragoonanan, V.; Suryanarayanan, R. Mol. Pharmaceutics 2016, 13 (4), 1339−1346. (26) Newman, A.; Zografi, G. J. Pharm. Sci. 2014, 103 (9), 2595− 2604.
interest (150 MPa, 5 s dwell time). However, PVP, even at very low concentration (1% w/w), prevented crystallization. At higher polymer concentrations (>10% w/w) even nucleation was inhibited. The “plasticization state” of the amorphous material influenced the effect of compression-induced destabilization. In general, an increase in plasticization directly translated to lower physical stability of the compressed amorphous phase. Again, the polymer, in a concentrationdependent matter, attenuated this amplifying effect on the compression-induced destabilization.
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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.7b01305. Figures containing (i) quantification example of XRD data, (ii) IR spectra of sucrose−PVP physical mixtures and respective ASDs of different compositions, and (iii) SXRD data of crystalline, amorphous “as is” and compressed sucrose samples (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Karlis ̅ Berziņ ̅ s:̌ 0000-0001-6545-5522 Raj Suryanarayanan: 0000-0002-6322-0575 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS K.B. was supported by the Baltic-American Freedom Foundation (BAFF) fellowship. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. Parts of this work were carried out in Characterization Facility, University of Minnesota, which receives partial support from NSF through the MSRC program. We thank Dr. Wenqian Xu at Argonne National Laboratory for his help during the synchrotron data collection. Dr. Naveen Thakral, Dr. Seema Thakral, Dr. Mehak Mehta, Dr. Pinal Mistry, Michelle Fung, and Sampada Koranne are thanked for their useful comments.
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DOI: 10.1021/acs.cgd.7b01305 Cryst. Growth Des. XXXX, XXX, XXX−XXX
