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Slow dissolution behaviour of amorphous capecitabine
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International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Slow dissolution behaviour of amorphous capecitabine Jelte Meulenaar a,c,∗ , Jos H. Beijnen a,b , Jan H.M. Schellens b,c , Bastiaan Nuijen a a
Department of Pharmacy & Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands c Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands b
a r t i c l e
i n f o
Article history: Received 25 October 2012 Received in revised form 22 November 2012 Accepted 26 November 2012 Available online xxx Keywords: Capecitabine Dissolution Amorphous Spray drying Slow release Recrystallization
a b s t r a c t In this article, we report the anomalous dissolution behaviour of amorphous capecitabine. In contrast to what is expected from thermodynamic theory, amorphous capecitabine dissolves significantly slower compared to its crystalline counterpart. Our experiments show that this is due to the “gelling” properties of amorphous capecitabine in an aqueous environment. The “gel”, which is immediately formed upon contact with water, entraps the capecitabine and significantly slows down its dissolution. This “gelling” property is hypothesized to be related to the low glass transition temperature (Tg 19 ◦ C) of amorphous capecitabine, resulting in an instant collapse (“gelling”) in an aqueous environment. From IR and DSC analysis it is shown that this collapsed capecitabine is remarkably stable and does not recrystallize upon an increased water content or temperature. This highly reproducible dissolution behaviour can be applied in the development of a sustained release dosage form as substantially less sustained release excipient is required in order to attain the desired release profile. As capecitabine is a high-dosed drug, this is highly favourable in view of the size and thus clinical feasibility of the final dosage form. Currently, we are developing and clinically testing a sustained release formulation making use of amorphous capecitabine and its remarkable dissolution behaviour. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Capecitabine (Fig. 1) is an orally administered chemotherapeutic agent used in the treatment of a.o. metastatic breast and colorectal cancers and is commercially available as an immediate release tablet (Xeloda® , Roche) (Roche Pharmaceuticals Inc., 2006). Capecitabine is a pre-pro-drug that is enzymatically converted into 5-fluorouracil (5-FU) in the tumour, where it inhibits DNA synthesis and slows growth of tumour tissue. To form 5-FU, the activation of capecitabine follows a three-step enzymatic pathway with two intermediary metabolites, 5 -deoxy-5-fluorocytidine (5 -DFCR) and 5 -deoxy-5-fluorouridine (5 -DFUR). The metabolism of capecitabine to 5-FU is quick (Cmax 60 min) and follows the pharmacokinetic profile of capecitabine. Subsequently, 5-FU is cleared rapidly and is undetectable in plasma after approximately six hours (Pentheroudakis and Twelves, 2002; Schellens, 2007; Walko and Lindley, 2005). Therefore, it is argued that the approved twice daily dosing (morning-evening) schedule of capecitabine results in an inbetween dosing capecitabine-exposure gap of approximately six hours. Clinical studies have shown that, as a consequence of the
∗ Corresponding author at: Department of Pharmacy & Pharmacology, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. Tel.: +31 020 512 47 31. E-mail address: [email protected] (J. Meulenaar).
prolonged exposure and reduction of the 5-FU peak plasma concentration, a continuous infusion instead of a bolus injection of 5-FU increases the anti-cancer response rate and decreases toxicity in terms of a reduced occurrence and grade of some adverse events (Meta-analysis Group In Cancer, 1998). In order to translate this concept to an oral dosing scheme, an extended release oral dosage form of capecitabine is warranted. For most active pharmaceutical ingredients (API) the development of a sustained release formulation is quite straightforward. Numerous excipients are commercially available (e.g. Kollidon® SR, BASF; Ethyl cellulose and ethylene oxide, Colorcon and the Poly(meth)acrylates, Evonik) which, by simply mixing with the API in a certain ratio followed by e.g. direct compression into tablets, results in a sustained release of the compound of interest. However, a prerequisite for this is that the API by itself has good compression characteristics, in particular for high-dosed APIs as because of size, little space per dose unit is available for additives. For example, Xeloda® consists of oblong shaped immediate release (IR) tablets containing 150 mg or 500 mg of capecitabine at a total weight of 187.5 mg and 625 mg, respectively, corresponding to 80% API and only 20% of excipients. Given the standard dosing regimen up to 1250 mg/m2 capecitabine twice daily, it is easily understood that from a patient compliance perspective this leaves little room for additional excipients which would result in either an increase in size or number of tablets. In this article we describe an unexpected finding during the development of an extended release
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2.2.3. Resistance to crushing Crushing strength was determined using an tensile strength tester Erweka TBH20 (Erweka, Heusenstamm, Germany). Tablets were placed flat faced in the holder.
Fig. 1. Chemical structure of Capecitabine (Mw 359.35 g/mol).
formulation of capecitabine. It is shown that spray-dried, amorphous capecitabine has significant delayed dissolution characteristics in vitro. To our knowledge, this anomalous dissolution behaviour is not previously reported. 2. Materials and methods 2.1. Materials Capecitabine drug substance (DS), manufactured by Jiangsu ZW Pharmaceuticals Co. (Changzhou, Jiangsu, China) was supplied by Dolder AG (Basel, Switzerland). Kollidon® SR was kindly provided by BASF (Limburgerhof, Germany). Xeloda® was purchased from Roche Laboratories Inc. (Nutley, NJ). All other excipients and solvents (analytical grade) originated from commercial suppliers. 2.2. Methods 2.2.1. Spray drying Capecitabine was spray-dried using a Büchi Mini Spray Dryer B-290, Inert Loop B-295, Dehumidifier B-296, High Performance cyclone, 1.5 mm nozzle cap, 0.7 mm nozzle tip (BUCHI Labortechnik AG, Flawil, Switserland). Spray dry system settings: Spray feed 15%; N2 atomization flow 40 mm (bottom of the ball); aspirator flow 80%; inlet temperature 18 ◦ C; outlet temperature 18 ◦ C; inert loop temperature −20 ◦ C. The capecitabine (40–65 g/L) was dissolved in 100% Ethanol (HPLC grade) and the solution was stirred using a magnetic stirrer. 2.2.2. Formulations, physical mixing and tablet compaction Table 1 shows qualitative and quantitative compositions of the tablets prepared. Powder mixtures were prepared by mixing the various components for 10 min in a gallipot using a TURBULA® – T 10 B (Willy A. Bachofen AG – Maschinenfabrik, Muttenz, Switzerland). If magnesium stearate was used this was separately blended with the powder mixture for maximal one minute just before tablet compaction. Tablet compaction was performed with a Korsch EK0 eccentric press (Korsch AG, Berlin, Germay). Tablets (9 mm Ø, resistance to crushing 60 N) were pressed using an amount of the formulation mixture equivalent to 224 mg capecitabine. Tablet thickness was related to the volume and compaction properties of the compacted powder.
2.2.4. Fourier transform infrared spectroscopy Infrared spectra were recorded from 650 to 4000 cm−1 with a resolution of 2 cm−1 with a FT-IR 8400S Spectrophotometer equipped with a golden gate® (Shimadzu, ‘s-Hertogenbosch, The Netherlands). A total of 64 scans were averaged into one spectrum. 2.2.5. Differential scanning calorimetry DSC measurements were performed with a Q2000 differential scanning calorimeter (TA Instruments, New Castle, DE, USA). Temperature scale and heat flow were calibrated with indium. Samples of approximately 10 mg powder were weighed into Tzero aluminium pans (TA instruments, New Castle, DE, USA), sealed and placed in the autosampler. Each sample was equilibrated at −20.00 ◦ C for 5 min, after which the sample was heated to 140.00 ◦ C at a speed of 10.00 ◦ C/min. 2.2.6. X-ray powder diffraction X-ray powder diffraction measurements were performed with an X’pert pro diffractometer equipped with an X-celerator (PANanalytical, Almelo, The Netherlands). Samples were placed in a 0.5 mm deep metal sample holder which was placed in the diffractometer. Samples were scanned at a current of 50 mA and a tension of 40 kV. The scanning range was 10–60◦ 2, with a step size of 0.020◦ and a scanning speed of 0.002◦ per second. 2.2.7. Dissolution testing Dissolution testing of the tablets was executed according to capecitabine monograph as published in the United States Pharmacopeia (USP) (Marques and Mao, 2011) using a type 2 (paddle) dissolution apparatus (Erweka, Heusenstamm, Germany) with Water for Injections (WfI) at 37 ◦ C as medium, stirred at 50 rpm. The dissolution test was continued until the point of 100% dissolution or until the % dissolved reached a constant level. Samples collected at the various time points were filtrated using a 0.45-m filter and subsequently analyzed on a reversed phase HPLC system with UV detection (RP-HPLC–UV) column: Varian, Inertsil ODS3, 15 cm × 4.6 mm; 5 m, Eluent Methanol:water (7:3, v/v), flow: 1.0 ml/min, detection: 310 nm. The retention time of capecitabine in this RP-HPLC–UV system is about 3.5 min. 2.2.8. Disintegration testing Tablet disintegration testing was performed using a USP compendial disintegration tester using discs (Erweka, Heusenstamm, Germany). The medium consisted of 600 mL WfI (B. Braun, Melsungen, Germany). Medium temperature was kept at 37 ◦ C. The penetration of disintegration medium into the tablet matrix was
Table 1 Tablet compositions. A: reference formulation Xeloda® ; formulations B–H all physically mixed; DS = drug substance. Active component/excipient
Tablet formulations A (Xeloda® )
Capecitabine Capecitabine DS Capecitabine spray-dried Capecitabine content Anhydrous lactose Croscarmellose sodium Hypromellose Microcrystalline cellulose Magnesium stearate Kollidon® SR
B
C
D
224 mg 79.98 (%) 8.32 (%) 4.42 (%) 2.00 (%) 3.84 (%) 1.44 (%)
224 mg 100 (%)
E
F
G
H
500 mg 224 mg 79.98 (%) 8.32 (%) 4.42 (%) 2.00 (%) 3.84 (%) 1.44 (%)
79.98 (%) 8.32 (%) 4.42 (%) 2.00 (%) 3.84 (%) 1.44 (%)
224 mg
224 mg
80 (%)
224 mg 80 (%)
60 (%)
224 mg 60 (%)
20 (%)
20 (%)
40 (%)
40 (%)
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Fig. 2. Dissolution profiles (n = 3) of capecitabine tablet formulations: A (, Xeloda® ), B (䊉, capecitabine DS), C (, spray-dried capecitabine), and D (, 100% spray-dried capecitabine). See Table 1 for the exact compositions.
examined using crystal violet (±1 g) added to the medium. Tablets were withdrawn from the bath after 0.25, 0.5, 1, 2, 8, 9 and 24 h. Immediately thereafter the tablets were visually inspected and cut in half to track the penetration of medium and photographed on a grid to measure tablet size. 3. Results 3.1. Compaction and dissolution behaviour Capecitabine (Fig. 1) is currently marketed as an immediate release tablet (Xeloda® , see Table 1, formulation A). As part of the development of a sustained release formulation, we examined the compaction characteristics of capecitabine DS. Using the Xeloda-formulation composition, compaction turned out to be difficult (Table 1, formulation B). Weak tablets with a maximal crushing strength of 60 N could be produced. A high percentage of these tablets showed capping and lamination during and after compaction, indicative for the poor binding properties of capecitabine DS, causing elastic deformation, in combination with poor flowability and, resulting in a buildup of internal pressure due to entrapped air during the compression (Aulton, 2002; Van der Voort Maarschalk et al., 1997). In order to improve both the binding and powder-flow characteristics, capecitabine DS was then spray-dried (Sebhatu and Alderborn, 1999). Indeed, spray drying of capecitabine DS resulted in a uniform, free-flowing powder which, alone or blended with excipients was easy to compact. Using relatively low compaction forces, tablets with high crushing strengths (240 N) could be produced without capping or lamination. However, we also found a significantly changed dissolution profile of spray-dried capecitabine compared to capecitabine DS. Fig. 2 shows the dissolution profiles of Xeloda® tablets (formulation A) compared to the exact same formulation composition only using capecitabine DS or spray-dried capecitabine (formulations B and C), and a formulation composed of spray-dried capecitabine only (formulation D). Clearly, the dissolution rate of tablets containing spray-dried capecitabine is significantly decreased compared to the Xeloda® reference formulation or the tablets containing capecitabine DS, resulting in an approximately 8-fold increase in t50% dissolution comparing formulation B and C. The slight difference between the dissolution profiles of the capecitabine DS formulation (formulation B) and Xeloda® , which dissolves slightly slower, is likely due to an alternative pre-treatment (e.g. wet granulation)
Fig. 3. Characterization of capecitabine DS (A1–C1) and spray-dried capecitabine (A2–C2) by FTIR, DSC and XRD. Characterization of gellified spray-dried capecitabine (A3) by FTIR and powdered Xeloda® (B3) by DSC.
of the capecitabine DS or formulation blend in order to improve tabletting characteristics. All the formulations reached 100% dissolution relative to their label claim. 3.2. Physical characterization Capecitabine DS and spray-dried capecitabine were physically examined using FTIR, DSC and XRD analysis (Fig. 3).
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The FTIR spectrum of the spray-dried capecitabine clearly shows less and less sharper peaks compared to the spectrum of the capecitabine DS (Fig. 3A1 and 3A2). The DSC thermogram of the capecitabine DS (Fig. 3B1) shows a clear melting peak (Tm ) at 121 ◦ C. In contrast, the DSC spectrum of the spray-dried capecitabine shows a glass transition temperature (Tg ) at around 19 ◦ C (Fig. 3B2). The XRD spectrum of capecitabine DS (Fig. 3C1) shows sharp refraction peaks which have completely disappeared in the spectrum of spray-dried capecitabine (Fig. 3C2). Additionally, a Xeloda® -tablet was powdered with mortar and pestle and physically characterized by FTIR (data not shown) and DSC (Fig. 3B3) analysis, resulting in similar spectra as those obtained with capecitabine DS as shown in Fig. 3A1 and B1. From these analyses it can be concluded that capecitabine DS is crystalline and becomes amorphous after spray-drying. Furthermore, the Xeloda® tablet formulation contains crystalline capecitabine.
4. Discussion
Fig. 4. DSC analysis of spray-dried amorphous capecitabine, heated to +80 ◦ C, subsequently kept isothermal at +80 ◦ C for 48 h (insert) and thereafter heated to +140 ◦ C.
From the results obtained it can be concluded that upon spraydrying capecitabine DS turns into its amorphous state. This is not unexpected, and many examples are available of compounds becoming at least partially amorphous upon spray-drying which is utilized e.g. in the development of solid dispersions (Leuner and Dressman, 2000; Moes et al., 2011). The fact, however, that the amorphous capecitabine displays significantly slower dissolution characteristics as compared to its crystalline counterpart was quite unexpected. Usually, the dissolution rate of a compound increases when converted into its amorphous state. The amorphous state is characterized by molecules being randomly ordered in a higher, less favourable energetic state compared to the long-range ordered crystalline structure. As this amorphous state is intrinsically thermodynamically unstable, less energy is needed to break the bonds between the molecules and therefore dissolution will be faster compared to crystalline material (Kaushal et al., 2004). However, we found an 8 fold increase in t50% dissolution dissolution time and a more than 6 h delay until complete dissolution when using amorphous instead of crystalline capecitabine (Fig. 2, formulation B versus C). Upon visual examination it appeared that the tablets containing amorphous capecitabine, in contrast to those containing crystalline DS, do not disintegrate but “gellify” and remain intact upon dissolution testing (paddle apparatus), slowly releasing the capecitabine content. As the tested formulations further only consisted of standard, immediate release excipients (Table 1), this behaviour can exclusively be attributed to the amorphous state of capecitabine. However upon disintegration testing the “gel” falls apart, having not a sufficiently strong matrix. Previously, several authors have reported anomalous dissolution behaviour of amorphous compounds in the context of solid dispersion formulations (Langham et al., 2012; Van Drooge et al., 2004). Langham et al. (2012) showed that when increasing the content of felodipine above 30% (w/w) in a spray-dried, amorphous solid dispersion formulation, the dissolution advantage provided by the formulation is lost in terms of dissolution time and extent, and is governed by the physical properties of felodipine. It was shown that upon dissolution testing as well as during compaction crystallization of felodipine occurs which is poorly water-soluble. Previously, Van Drooge et al. (2004) reported a similar result when examining the slow-dissolution behaviour of diazepam from a disaccharideglass based solid dispersion. Using DSC analysis, it appeared that amorphous diazepam rapidly crystallized upon contact with the aqueous dissolution medium, explaining the slow dissolution. However, these findings cannot be extrapolated to the dissolution
behaviour of amorphous capecitabine as crystalline capecitabine in contrast to the above mentioned compounds is highly watersoluble. Moreover, IR analysis of the “gellified” system formed upon dissolution testing showed a similar profile as obtained for amorphous capecitabine (Fig. 3A3), thus indicative that recrystallization does not occur. We therefore hypothesize that the “gellification” of amorphous capecitabine upon immersion in the dissolution bath is related to its low Tg of +19 ◦ C (Fig. 3B2), which, as a result of an increased water content, causes an instant collapse but no recrystallization. Indeed, the same “gelling” phenomenon is observed within 10 weeks when storing tablets containing amorphous capecitabine at room temperature (+20–25 ◦ C) which display unchanged dissolution profiles (data not shown). Additionally, the reluctance of amorphous capecitabine to recrystallize is illustrated using DSC analysis which showed no exothermal events even when heating from 0 ◦ C to +80 ◦ C and keeping the latter condition isothermical for 48 h (Fig. 4). In summary, upon dissolution testing, amorphous capecitabine forms a collapsed (“gellified”), but highly stable system in terms of recrystallization which slowly, but completely and highly reproducible dissolves in time in a delayed manner. In order to examine if this phenomenon still remains in the presence of a sustained release excipient, capecitabine tablets containing 20% (w/w) of Kollidon® SR were prepared using both capecitabine DS and spray-dried capecitabine (formulation E and F). From the dissolution curves depicted in Fig. 5 it can be seen that adding a sustained release excipient to capecitabine DS gives a significant delay in release with respect to Xeloda® (formulations A versus E). The addition of an equal amount of sustained release excipient to amorphous capecitabine results in even a more pronounced effect. The 15.6-fold increase in t50% dissolution of formulation A versus E compared to an 18.8-fold increase for formulation C versus F is indicative for a synergistic effect of amorphous capecitabine and Kollidon® SR in slowing down capecitabine dissolution. These results suggest that far less extended release excipient is required when using amorphous capecitabine in order to obtain the same dissolution profile when using crystalline capecitabine. In order to examine the dissolution behaviour from a visual perspective, tablets containing 40% (w/w) Kollidon® SR and either capecitabine DS or spray-dried capecitabine (formulations G and H, Table 1.) were subjected to a disintegration test using crystal violet as a penetration marker. As becomes clear from Fig. 6, tablets containing capecitabine DS decreased rapidly in size and after 60 min only one third of the total tablet is left with a complete
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dissolution. In view of the development of a sustained release oral dosage form of capecitabine this is attractive, as substantially less sustained release excipient is expected to be needed in order to attain the desired release profile. As capecitabine is a high-dosed drug, this is highly favourable in view of the size and thus clinical feasibility of the final dosage form. 5. Conclusion
Fig. 5. Dissolution profiles (n = 3) of capecitabine tablet formulations: A (, Xeloda® ), C (䊉, spray-dried capecitabine), E (, physical mixture of 20% Kollidon® SR and capecitabine DS) and F (, physical mixture of 20% Kollidon® SR and spray-dried capecitabine). See Table 1 for exact compositions. The insert shows the complete dissolution profile of formulation F.
In this article, we report the anomalous dissolution behaviour of amorphous capecitabine. In contrast to what is expected from thermodynamic theory, amorphous capecitabine dissolves significantly slower compared to its crystalline counterpart. The experiments performed show that this is due to the “gelling” properties of amorphous capecitabine in an aqueous environment. The “gel”, which is immediately formed upon contact with water, entraps the capecitabine and significantly slows down its dissolution. This “gelling” property is hypothesized to be related to the low glass transition temperature (Tg 19 ◦ C) of amorphous capecitabine, resulting in an instant collapse (“gelling”) in an aqueous environment. From IR and DSC analysis it is shown that this collapsed capecitabine is remarkably stable and does not recrystallize upon an increased water content or temperature. This highly reproducible dissolution behaviour can be applied in the development of a sustained release dosage form as substantially less sustained release excipient is required in order to attain the desired release profile. As capecitabine is a high-dosed drug, this is highly favourable in view of the size and thus clinical feasibility of the final dosage form. However, the low Tg of amorphous capecitabine also poses a challenge from a shelf-life stability perspective. Currently, we are developing and clinically testing a sustained release formulation making use of amorphous capecitabine and its remarkable dissolution behaviour. References
Fig. 6. Pictures of tablets containing 40% (w/w) Kollidon® SR and 60% (w/w) crystalline or amorphous capecitabine during disintegration testing (t = 0, 15 and 60 min) with crystal violet stained medium. Thickness of initial tablets (t = 0) reflects the difference in compaction behaviour of crystalline and amorphous capecitabine.
dissolution after 120 min. The disintegration clearly takes place by erosion of the tablet. No penetration of disintegration medium into the tablet core occurs as the purple marker only deposits on the exterior of the tablet with no discoloration of the core. In contrast, the disintegration test of the tablet containing 60% spray dried capecitabine and 40% Kollidon® SR (Fig. 6) shows different results. Indeed, as observed for the immediate release formulation compositions, “gelling” of the tablet is observed, although only at the exterior of the tablet. In contrast, the tablet remains intact during the disintegration test and limited swelling takes place. The latter is indicative for the hydration and matrix formation of the Kollidon® SR, composed of polyvinyl acetate and povidone. From these results it can be concluded that the slow dissolution characteristics of amorphous capecitabine remain upon the addition of Kollidon® SR, a commercially available extended-release excipient. Moreover, amorphous capecitabine and Kollidon® SR appear to act synergistically in slowing down capecitabine
Aulton, M., 2002. Pharmaceutics, the Science of Dosage from Design, second ed. Churchill Livingstone, Edinburgh. Kaushal, A.M., Gupta, P., Bansal, A.K., 2004. Amorphous drug delivery systems: molecular aspects, design, and performance. Crit. Rev. Ther. Drug Carrier Syst. 21, 133–193. Langham, Z.A., Booth, J., Hughes, L.P., Reynolds, G.K., Wren, S.A.C., 2012. Mechanistic insights into the dissolution of spray-dried amorphous solid dispersions. J. Pharm. Sci. 101, 2798–2810. Leuner, C., Dressman, J., 2000. Improving drug solubility for oral delivery using solid dispersions. Eur. J. Pharm. Biopharm. 50, 47–60. Marques, M.R.C, Mao, F., 2011. USP34-NF29, p. 2148. Meta-analysis Group In Cancer, 1998. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J. Clin. Oncol. 16, 301–308. Moes, J.J., Koolen, S.L.W., Huitema, A.D.R., Schellens, J.H.M., Beijnen, J.H., Nuijen, B., 2011. Pharmaceutical development and preliminary clinical testing of an oral solid dispersion formulation of docetaxel (ModraDoc001). Int. J. Pharm. 420, 244–250. Pentheroudakis, G., Twelves, C., 2002. Capecitabine (Xeloda): from the laboratory to the patient’s home. Clin. Colorectal Cancer 2, 16–23. Roche Pharmaceuticals Inc., 2006. Xeloda® Summary of Product Characteristics. Nutley, NJ. Schellens, J.H., 2007. Capecitabine. Oncologist 12, 152–155. Sebhatu, T., Alderborn, G., 1999. Relationships between the effective interparticulate contact area and the tensile strength of tablets of amorphous and crystalline lactose of varying particle size. Eur. J. Pharm. Sci. 8, 235–242. Van der Voort Maarschalk, K., Zuurman, K., Vromans, H., Bolhuis, G.K., Lerk, C.F., 1997. Stress relaxation of compacts produced from viscoelastic materials. Int. J. Pharm. 151, 27–34. Van Drooge, D.J., Hinrichs, W.L.J., Frijlink, H.W., 2004. Anomalous dissolution behaviour of tablets prepared from sugar glass-based solid dispersions. J. Control. Release 97, 441–452. Walko, C.M., Lindley, C., 2005. Capecitabine: a review. Clin. Ther. 27, 23–44.
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ARTICLE IN PRESS International Journal of Pharmaceutics xxx (2012) xxx–xxx
Contents lists available at SciVerse ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Slow dissolution behaviour of amorphous capecitabine Jelte Meulenaar a,c,∗ , Jos H. Beijnen a,b , Jan H.M. Schellens b,c , Bastiaan Nuijen a a
Department of Pharmacy & Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands c Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands b
a r t i c l e
i n f o
Article history: Received 25 October 2012 Received in revised form 22 November 2012 Accepted 26 November 2012 Available online xxx Keywords: Capecitabine Dissolution Amorphous Spray drying Slow release Recrystallization
a b s t r a c t In this article, we report the anomalous dissolution behaviour of amorphous capecitabine. In contrast to what is expected from thermodynamic theory, amorphous capecitabine dissolves significantly slower compared to its crystalline counterpart. Our experiments show that this is due to the “gelling” properties of amorphous capecitabine in an aqueous environment. The “gel”, which is immediately formed upon contact with water, entraps the capecitabine and significantly slows down its dissolution. This “gelling” property is hypothesized to be related to the low glass transition temperature (Tg 19 ◦ C) of amorphous capecitabine, resulting in an instant collapse (“gelling”) in an aqueous environment. From IR and DSC analysis it is shown that this collapsed capecitabine is remarkably stable and does not recrystallize upon an increased water content or temperature. This highly reproducible dissolution behaviour can be applied in the development of a sustained release dosage form as substantially less sustained release excipient is required in order to attain the desired release profile. As capecitabine is a high-dosed drug, this is highly favourable in view of the size and thus clinical feasibility of the final dosage form. Currently, we are developing and clinically testing a sustained release formulation making use of amorphous capecitabine and its remarkable dissolution behaviour. © 2012 Elsevier B.V. All rights reserved.
1. Introduction Capecitabine (Fig. 1) is an orally administered chemotherapeutic agent used in the treatment of a.o. metastatic breast and colorectal cancers and is commercially available as an immediate release tablet (Xeloda® , Roche) (Roche Pharmaceuticals Inc., 2006). Capecitabine is a pre-pro-drug that is enzymatically converted into 5-fluorouracil (5-FU) in the tumour, where it inhibits DNA synthesis and slows growth of tumour tissue. To form 5-FU, the activation of capecitabine follows a three-step enzymatic pathway with two intermediary metabolites, 5 -deoxy-5-fluorocytidine (5 -DFCR) and 5 -deoxy-5-fluorouridine (5 -DFUR). The metabolism of capecitabine to 5-FU is quick (Cmax 60 min) and follows the pharmacokinetic profile of capecitabine. Subsequently, 5-FU is cleared rapidly and is undetectable in plasma after approximately six hours (Pentheroudakis and Twelves, 2002; Schellens, 2007; Walko and Lindley, 2005). Therefore, it is argued that the approved twice daily dosing (morning-evening) schedule of capecitabine results in an inbetween dosing capecitabine-exposure gap of approximately six hours. Clinical studies have shown that, as a consequence of the
∗ Corresponding author at: Department of Pharmacy & Pharmacology, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, The Netherlands. Tel.: +31 020 512 47 31. E-mail address: [email protected] (J. Meulenaar).
prolonged exposure and reduction of the 5-FU peak plasma concentration, a continuous infusion instead of a bolus injection of 5-FU increases the anti-cancer response rate and decreases toxicity in terms of a reduced occurrence and grade of some adverse events (Meta-analysis Group In Cancer, 1998). In order to translate this concept to an oral dosing scheme, an extended release oral dosage form of capecitabine is warranted. For most active pharmaceutical ingredients (API) the development of a sustained release formulation is quite straightforward. Numerous excipients are commercially available (e.g. Kollidon® SR, BASF; Ethyl cellulose and ethylene oxide, Colorcon and the Poly(meth)acrylates, Evonik) which, by simply mixing with the API in a certain ratio followed by e.g. direct compression into tablets, results in a sustained release of the compound of interest. However, a prerequisite for this is that the API by itself has good compression characteristics, in particular for high-dosed APIs as because of size, little space per dose unit is available for additives. For example, Xeloda® consists of oblong shaped immediate release (IR) tablets containing 150 mg or 500 mg of capecitabine at a total weight of 187.5 mg and 625 mg, respectively, corresponding to 80% API and only 20% of excipients. Given the standard dosing regimen up to 1250 mg/m2 capecitabine twice daily, it is easily understood that from a patient compliance perspective this leaves little room for additional excipients which would result in either an increase in size or number of tablets. In this article we describe an unexpected finding during the development of an extended release
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2.2.3. Resistance to crushing Crushing strength was determined using an tensile strength tester Erweka TBH20 (Erweka, Heusenstamm, Germany). Tablets were placed flat faced in the holder.
Fig. 1. Chemical structure of Capecitabine (Mw 359.35 g/mol).
formulation of capecitabine. It is shown that spray-dried, amorphous capecitabine has significant delayed dissolution characteristics in vitro. To our knowledge, this anomalous dissolution behaviour is not previously reported. 2. Materials and methods 2.1. Materials Capecitabine drug substance (DS), manufactured by Jiangsu ZW Pharmaceuticals Co. (Changzhou, Jiangsu, China) was supplied by Dolder AG (Basel, Switzerland). Kollidon® SR was kindly provided by BASF (Limburgerhof, Germany). Xeloda® was purchased from Roche Laboratories Inc. (Nutley, NJ). All other excipients and solvents (analytical grade) originated from commercial suppliers. 2.2. Methods 2.2.1. Spray drying Capecitabine was spray-dried using a Büchi Mini Spray Dryer B-290, Inert Loop B-295, Dehumidifier B-296, High Performance cyclone, 1.5 mm nozzle cap, 0.7 mm nozzle tip (BUCHI Labortechnik AG, Flawil, Switserland). Spray dry system settings: Spray feed 15%; N2 atomization flow 40 mm (bottom of the ball); aspirator flow 80%; inlet temperature 18 ◦ C; outlet temperature 18 ◦ C; inert loop temperature −20 ◦ C. The capecitabine (40–65 g/L) was dissolved in 100% Ethanol (HPLC grade) and the solution was stirred using a magnetic stirrer. 2.2.2. Formulations, physical mixing and tablet compaction Table 1 shows qualitative and quantitative compositions of the tablets prepared. Powder mixtures were prepared by mixing the various components for 10 min in a gallipot using a TURBULA® – T 10 B (Willy A. Bachofen AG – Maschinenfabrik, Muttenz, Switzerland). If magnesium stearate was used this was separately blended with the powder mixture for maximal one minute just before tablet compaction. Tablet compaction was performed with a Korsch EK0 eccentric press (Korsch AG, Berlin, Germay). Tablets (9 mm Ø, resistance to crushing 60 N) were pressed using an amount of the formulation mixture equivalent to 224 mg capecitabine. Tablet thickness was related to the volume and compaction properties of the compacted powder.
2.2.4. Fourier transform infrared spectroscopy Infrared spectra were recorded from 650 to 4000 cm−1 with a resolution of 2 cm−1 with a FT-IR 8400S Spectrophotometer equipped with a golden gate® (Shimadzu, ‘s-Hertogenbosch, The Netherlands). A total of 64 scans were averaged into one spectrum. 2.2.5. Differential scanning calorimetry DSC measurements were performed with a Q2000 differential scanning calorimeter (TA Instruments, New Castle, DE, USA). Temperature scale and heat flow were calibrated with indium. Samples of approximately 10 mg powder were weighed into Tzero aluminium pans (TA instruments, New Castle, DE, USA), sealed and placed in the autosampler. Each sample was equilibrated at −20.00 ◦ C for 5 min, after which the sample was heated to 140.00 ◦ C at a speed of 10.00 ◦ C/min. 2.2.6. X-ray powder diffraction X-ray powder diffraction measurements were performed with an X’pert pro diffractometer equipped with an X-celerator (PANanalytical, Almelo, The Netherlands). Samples were placed in a 0.5 mm deep metal sample holder which was placed in the diffractometer. Samples were scanned at a current of 50 mA and a tension of 40 kV. The scanning range was 10–60◦ 2, with a step size of 0.020◦ and a scanning speed of 0.002◦ per second. 2.2.7. Dissolution testing Dissolution testing of the tablets was executed according to capecitabine monograph as published in the United States Pharmacopeia (USP) (Marques and Mao, 2011) using a type 2 (paddle) dissolution apparatus (Erweka, Heusenstamm, Germany) with Water for Injections (WfI) at 37 ◦ C as medium, stirred at 50 rpm. The dissolution test was continued until the point of 100% dissolution or until the % dissolved reached a constant level. Samples collected at the various time points were filtrated using a 0.45-m filter and subsequently analyzed on a reversed phase HPLC system with UV detection (RP-HPLC–UV) column: Varian, Inertsil ODS3, 15 cm × 4.6 mm; 5 m, Eluent Methanol:water (7:3, v/v), flow: 1.0 ml/min, detection: 310 nm. The retention time of capecitabine in this RP-HPLC–UV system is about 3.5 min. 2.2.8. Disintegration testing Tablet disintegration testing was performed using a USP compendial disintegration tester using discs (Erweka, Heusenstamm, Germany). The medium consisted of 600 mL WfI (B. Braun, Melsungen, Germany). Medium temperature was kept at 37 ◦ C. The penetration of disintegration medium into the tablet matrix was
Table 1 Tablet compositions. A: reference formulation Xeloda® ; formulations B–H all physically mixed; DS = drug substance. Active component/excipient
Tablet formulations A (Xeloda® )
Capecitabine Capecitabine DS Capecitabine spray-dried Capecitabine content Anhydrous lactose Croscarmellose sodium Hypromellose Microcrystalline cellulose Magnesium stearate Kollidon® SR
B
C
D
224 mg 79.98 (%) 8.32 (%) 4.42 (%) 2.00 (%) 3.84 (%) 1.44 (%)
224 mg 100 (%)
E
F
G
H
500 mg 224 mg 79.98 (%) 8.32 (%) 4.42 (%) 2.00 (%) 3.84 (%) 1.44 (%)
79.98 (%) 8.32 (%) 4.42 (%) 2.00 (%) 3.84 (%) 1.44 (%)
224 mg
224 mg
80 (%)
224 mg 80 (%)
60 (%)
224 mg 60 (%)
20 (%)
20 (%)
40 (%)
40 (%)
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Fig. 2. Dissolution profiles (n = 3) of capecitabine tablet formulations: A (, Xeloda® ), B (䊉, capecitabine DS), C (, spray-dried capecitabine), and D (, 100% spray-dried capecitabine). See Table 1 for the exact compositions.
examined using crystal violet (±1 g) added to the medium. Tablets were withdrawn from the bath after 0.25, 0.5, 1, 2, 8, 9 and 24 h. Immediately thereafter the tablets were visually inspected and cut in half to track the penetration of medium and photographed on a grid to measure tablet size. 3. Results 3.1. Compaction and dissolution behaviour Capecitabine (Fig. 1) is currently marketed as an immediate release tablet (Xeloda® , see Table 1, formulation A). As part of the development of a sustained release formulation, we examined the compaction characteristics of capecitabine DS. Using the Xeloda-formulation composition, compaction turned out to be difficult (Table 1, formulation B). Weak tablets with a maximal crushing strength of 60 N could be produced. A high percentage of these tablets showed capping and lamination during and after compaction, indicative for the poor binding properties of capecitabine DS, causing elastic deformation, in combination with poor flowability and, resulting in a buildup of internal pressure due to entrapped air during the compression (Aulton, 2002; Van der Voort Maarschalk et al., 1997). In order to improve both the binding and powder-flow characteristics, capecitabine DS was then spray-dried (Sebhatu and Alderborn, 1999). Indeed, spray drying of capecitabine DS resulted in a uniform, free-flowing powder which, alone or blended with excipients was easy to compact. Using relatively low compaction forces, tablets with high crushing strengths (240 N) could be produced without capping or lamination. However, we also found a significantly changed dissolution profile of spray-dried capecitabine compared to capecitabine DS. Fig. 2 shows the dissolution profiles of Xeloda® tablets (formulation A) compared to the exact same formulation composition only using capecitabine DS or spray-dried capecitabine (formulations B and C), and a formulation composed of spray-dried capecitabine only (formulation D). Clearly, the dissolution rate of tablets containing spray-dried capecitabine is significantly decreased compared to the Xeloda® reference formulation or the tablets containing capecitabine DS, resulting in an approximately 8-fold increase in t50% dissolution comparing formulation B and C. The slight difference between the dissolution profiles of the capecitabine DS formulation (formulation B) and Xeloda® , which dissolves slightly slower, is likely due to an alternative pre-treatment (e.g. wet granulation)
Fig. 3. Characterization of capecitabine DS (A1–C1) and spray-dried capecitabine (A2–C2) by FTIR, DSC and XRD. Characterization of gellified spray-dried capecitabine (A3) by FTIR and powdered Xeloda® (B3) by DSC.
of the capecitabine DS or formulation blend in order to improve tabletting characteristics. All the formulations reached 100% dissolution relative to their label claim. 3.2. Physical characterization Capecitabine DS and spray-dried capecitabine were physically examined using FTIR, DSC and XRD analysis (Fig. 3).
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The FTIR spectrum of the spray-dried capecitabine clearly shows less and less sharper peaks compared to the spectrum of the capecitabine DS (Fig. 3A1 and 3A2). The DSC thermogram of the capecitabine DS (Fig. 3B1) shows a clear melting peak (Tm ) at 121 ◦ C. In contrast, the DSC spectrum of the spray-dried capecitabine shows a glass transition temperature (Tg ) at around 19 ◦ C (Fig. 3B2). The XRD spectrum of capecitabine DS (Fig. 3C1) shows sharp refraction peaks which have completely disappeared in the spectrum of spray-dried capecitabine (Fig. 3C2). Additionally, a Xeloda® -tablet was powdered with mortar and pestle and physically characterized by FTIR (data not shown) and DSC (Fig. 3B3) analysis, resulting in similar spectra as those obtained with capecitabine DS as shown in Fig. 3A1 and B1. From these analyses it can be concluded that capecitabine DS is crystalline and becomes amorphous after spray-drying. Furthermore, the Xeloda® tablet formulation contains crystalline capecitabine.
4. Discussion
Fig. 4. DSC analysis of spray-dried amorphous capecitabine, heated to +80 ◦ C, subsequently kept isothermal at +80 ◦ C for 48 h (insert) and thereafter heated to +140 ◦ C.
From the results obtained it can be concluded that upon spraydrying capecitabine DS turns into its amorphous state. This is not unexpected, and many examples are available of compounds becoming at least partially amorphous upon spray-drying which is utilized e.g. in the development of solid dispersions (Leuner and Dressman, 2000; Moes et al., 2011). The fact, however, that the amorphous capecitabine displays significantly slower dissolution characteristics as compared to its crystalline counterpart was quite unexpected. Usually, the dissolution rate of a compound increases when converted into its amorphous state. The amorphous state is characterized by molecules being randomly ordered in a higher, less favourable energetic state compared to the long-range ordered crystalline structure. As this amorphous state is intrinsically thermodynamically unstable, less energy is needed to break the bonds between the molecules and therefore dissolution will be faster compared to crystalline material (Kaushal et al., 2004). However, we found an 8 fold increase in t50% dissolution dissolution time and a more than 6 h delay until complete dissolution when using amorphous instead of crystalline capecitabine (Fig. 2, formulation B versus C). Upon visual examination it appeared that the tablets containing amorphous capecitabine, in contrast to those containing crystalline DS, do not disintegrate but “gellify” and remain intact upon dissolution testing (paddle apparatus), slowly releasing the capecitabine content. As the tested formulations further only consisted of standard, immediate release excipients (Table 1), this behaviour can exclusively be attributed to the amorphous state of capecitabine. However upon disintegration testing the “gel” falls apart, having not a sufficiently strong matrix. Previously, several authors have reported anomalous dissolution behaviour of amorphous compounds in the context of solid dispersion formulations (Langham et al., 2012; Van Drooge et al., 2004). Langham et al. (2012) showed that when increasing the content of felodipine above 30% (w/w) in a spray-dried, amorphous solid dispersion formulation, the dissolution advantage provided by the formulation is lost in terms of dissolution time and extent, and is governed by the physical properties of felodipine. It was shown that upon dissolution testing as well as during compaction crystallization of felodipine occurs which is poorly water-soluble. Previously, Van Drooge et al. (2004) reported a similar result when examining the slow-dissolution behaviour of diazepam from a disaccharideglass based solid dispersion. Using DSC analysis, it appeared that amorphous diazepam rapidly crystallized upon contact with the aqueous dissolution medium, explaining the slow dissolution. However, these findings cannot be extrapolated to the dissolution
behaviour of amorphous capecitabine as crystalline capecitabine in contrast to the above mentioned compounds is highly watersoluble. Moreover, IR analysis of the “gellified” system formed upon dissolution testing showed a similar profile as obtained for amorphous capecitabine (Fig. 3A3), thus indicative that recrystallization does not occur. We therefore hypothesize that the “gellification” of amorphous capecitabine upon immersion in the dissolution bath is related to its low Tg of +19 ◦ C (Fig. 3B2), which, as a result of an increased water content, causes an instant collapse but no recrystallization. Indeed, the same “gelling” phenomenon is observed within 10 weeks when storing tablets containing amorphous capecitabine at room temperature (+20–25 ◦ C) which display unchanged dissolution profiles (data not shown). Additionally, the reluctance of amorphous capecitabine to recrystallize is illustrated using DSC analysis which showed no exothermal events even when heating from 0 ◦ C to +80 ◦ C and keeping the latter condition isothermical for 48 h (Fig. 4). In summary, upon dissolution testing, amorphous capecitabine forms a collapsed (“gellified”), but highly stable system in terms of recrystallization which slowly, but completely and highly reproducible dissolves in time in a delayed manner. In order to examine if this phenomenon still remains in the presence of a sustained release excipient, capecitabine tablets containing 20% (w/w) of Kollidon® SR were prepared using both capecitabine DS and spray-dried capecitabine (formulation E and F). From the dissolution curves depicted in Fig. 5 it can be seen that adding a sustained release excipient to capecitabine DS gives a significant delay in release with respect to Xeloda® (formulations A versus E). The addition of an equal amount of sustained release excipient to amorphous capecitabine results in even a more pronounced effect. The 15.6-fold increase in t50% dissolution of formulation A versus E compared to an 18.8-fold increase for formulation C versus F is indicative for a synergistic effect of amorphous capecitabine and Kollidon® SR in slowing down capecitabine dissolution. These results suggest that far less extended release excipient is required when using amorphous capecitabine in order to obtain the same dissolution profile when using crystalline capecitabine. In order to examine the dissolution behaviour from a visual perspective, tablets containing 40% (w/w) Kollidon® SR and either capecitabine DS or spray-dried capecitabine (formulations G and H, Table 1.) were subjected to a disintegration test using crystal violet as a penetration marker. As becomes clear from Fig. 6, tablets containing capecitabine DS decreased rapidly in size and after 60 min only one third of the total tablet is left with a complete
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dissolution. In view of the development of a sustained release oral dosage form of capecitabine this is attractive, as substantially less sustained release excipient is expected to be needed in order to attain the desired release profile. As capecitabine is a high-dosed drug, this is highly favourable in view of the size and thus clinical feasibility of the final dosage form. 5. Conclusion
Fig. 5. Dissolution profiles (n = 3) of capecitabine tablet formulations: A (, Xeloda® ), C (䊉, spray-dried capecitabine), E (, physical mixture of 20% Kollidon® SR and capecitabine DS) and F (, physical mixture of 20% Kollidon® SR and spray-dried capecitabine). See Table 1 for exact compositions. The insert shows the complete dissolution profile of formulation F.
In this article, we report the anomalous dissolution behaviour of amorphous capecitabine. In contrast to what is expected from thermodynamic theory, amorphous capecitabine dissolves significantly slower compared to its crystalline counterpart. The experiments performed show that this is due to the “gelling” properties of amorphous capecitabine in an aqueous environment. The “gel”, which is immediately formed upon contact with water, entraps the capecitabine and significantly slows down its dissolution. This “gelling” property is hypothesized to be related to the low glass transition temperature (Tg 19 ◦ C) of amorphous capecitabine, resulting in an instant collapse (“gelling”) in an aqueous environment. From IR and DSC analysis it is shown that this collapsed capecitabine is remarkably stable and does not recrystallize upon an increased water content or temperature. This highly reproducible dissolution behaviour can be applied in the development of a sustained release dosage form as substantially less sustained release excipient is required in order to attain the desired release profile. As capecitabine is a high-dosed drug, this is highly favourable in view of the size and thus clinical feasibility of the final dosage form. However, the low Tg of amorphous capecitabine also poses a challenge from a shelf-life stability perspective. Currently, we are developing and clinically testing a sustained release formulation making use of amorphous capecitabine and its remarkable dissolution behaviour. References
Fig. 6. Pictures of tablets containing 40% (w/w) Kollidon® SR and 60% (w/w) crystalline or amorphous capecitabine during disintegration testing (t = 0, 15 and 60 min) with crystal violet stained medium. Thickness of initial tablets (t = 0) reflects the difference in compaction behaviour of crystalline and amorphous capecitabine.
dissolution after 120 min. The disintegration clearly takes place by erosion of the tablet. No penetration of disintegration medium into the tablet core occurs as the purple marker only deposits on the exterior of the tablet with no discoloration of the core. In contrast, the disintegration test of the tablet containing 60% spray dried capecitabine and 40% Kollidon® SR (Fig. 6) shows different results. Indeed, as observed for the immediate release formulation compositions, “gelling” of the tablet is observed, although only at the exterior of the tablet. In contrast, the tablet remains intact during the disintegration test and limited swelling takes place. The latter is indicative for the hydration and matrix formation of the Kollidon® SR, composed of polyvinyl acetate and povidone. From these results it can be concluded that the slow dissolution characteristics of amorphous capecitabine remain upon the addition of Kollidon® SR, a commercially available extended-release excipient. Moreover, amorphous capecitabine and Kollidon® SR appear to act synergistically in slowing down capecitabine
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