- Email: [email protected]
Towards Effective Solid Form Screening
Towards Effective Solid Form Screening MORTEN ALLESØ, FANG TIAN, CLAUS CORNETT, JUKKA RANTANEN Faculty of Pharmaceutical Sciences, Department of Pharmaceutics and Analytical Chemistry, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark Received 6 April 2009; revised 18 August 2009; accepted 19 August 2009 Published online 1 October 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21957 ABSTRACT: Solid form screening is commonly performed using solvent-based crystallizations. However, less attention is paid to the role of secondary manufacturing, during which processinduced transformations of the active pharmaceutical ingredient (API) may occur, and potentially a new solid form may be discovered. In this study a new approach for effective solid form screening is presented. The technology combines well-plate-based crystallizations with miniaturized processing equipment, mimicking essential unit operations. Process-induced stresses (heat, solvent, shear, pressure) can be introduced directly to the well-plate unit. Theophylline and nifedipine were used as model compounds. Small-scale wet massing of theophylline resulted in an anhydrate-to-monohydrate transformation, followed by dehydration upon drying at 608C. Amorphous nifedipine was subjected to small-scale milling and compaction. Kinetic profiling of the milling operation enabled the detection of an intermediate, metastable polymorph (b form), while the stable polymorph (a form) was the predominant form after 20 min of milling. Compaction of amorphous nifedipine at 100 MPa resulted in a complete conversion into the stable polymorph. The reported expanded approach is expected to maximize the outcome of solid form screening with minimal consumption of the compound of interest. ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3711–3718, 2010
Keywords: polymorph screening; hydrate; amorphous; process-induced transformations (PITs); high throughput; near-infrared (NIR) spectroscopy; Raman spectroscopy; theophylline; nifedipine
INTRODUCTION Polymorphism, that is, the ability of a solid to exist in more than one crystal structure,1 is an area of great interest and concern to the pharmaceutical industry. The reasons for this are related to (1) product quality and performance, as polymorphs often show varying dissolution behavior, stability, and processability, and (2) financial aspects, since each polymorph is patentable.2 Solids may also exist as amorphous material with no long-range order. Likewise, the active pharmaceutical ingredient (API) molecule may coexist with a guest molecule. The crystal forms are designated a solvate or a cocrystal, when the guest molecule is a liquid or solid at room temperature, respectively. Salts are distinguished from all other forms by being stabilized by ionic bonding between API and guest molecule. To avoid term confusion, all above-mentioned solid modifications (i.e., polymorphs, amorphous material, solvates, cocrystals) Correspondence to: Jukka Rantanen (Telephone: þ45-35336000; Fax: þ45-35336030; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 99, 3711–3718 (2010) ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association
are henceforth referred to as solid forms. It is crucial to perform a thorough and reliable solid form screening at the early stage of preformulation. The objective of this screening is to find as many solid forms as possible and to identify the most suitable form for further development.3 In most cases the stable form is desired, though a need for enhanced dissolution rate may sometimes lead to the manufacture of a metastable crystalline form or amorphous material.4 However, no matter how thorough a screening, the burning question still remains: Has the most stable form actually been found? This is often not possible to answer with absolute confidence, as metastable forms may remain in their structural arrangement for a relatively long time. A startling example of an appearing new polymorphic form is the case of ritonavir, a peptidomimetic drug used to treat HIV-1 infection and introduced in 1996 (Norvir, Abbott Laboratories, Chicago, IL).5 During development and initial manufacture of ritonavir, only one monoclinic crystal form was known. In 1998, a lower energy, more stable form (form II) appeared, causing slower dissolution. Two years after entry into the market, several lots of Norvir capsules began failing dissolution specifications. Evaluation of the failed
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drug products revealed that a second and more stable crystal form of ritonavir (form II) had precipitated from the formulation. At some considerable cost a new formulation of Norvir was eventually developed and launched. This illustrates the importance of conducting a well-designed and thorough screening, properly spanning the multiparameter space that contributes to API solid form diversity. There is no specific methodology available for performing polymorph screening.6 This is mostly due to the poor understanding of nucleation and crystal growth phenomena, which underlines the need for experimental approaches in this field. The use of automated highthroughput technology has become widely popular.7 The main advantage of high-throughput systems lies in the large number of crystallizations carried out (several hundreds in a single run), which in addition utilize low API quantities and little if no manual intervention. This allows for large experimental designs where several factors are varied, including heating rate, cooling rate, degree of supersaturation, solvent type, etc. However, poor API solubility in some solvents often results in low hit rates for these systems (between 2.5% and 13%).8–10 Manual benchscale crystallizations are used to solve the issue of low solubility, utilizing larger solvent volumes and thus more API. However, current high-throughput as well as bench-scale technology suffer from one major drawback: They do not take into account the impact of secondary manufacturing on API polymorphism. Stresses encountered during manufacturing are well known to be able to cause process-induced transformations (PITs) of the initial API solid form which ultimately may lead to altered product attributes.11– 13 During pharmaceutical unit operations, processinduced stresses originate from temperature (e.g., drying phase), mechanical activation (e.g., milling, compression), or water/solvate (e.g., wet granulation). The anhydrate-to-hydrate conversion of theophylline during wet granulation has been reported,14,15 while Wardrop et al.16 observed an anhydrate-to-amorphous conversion of the uroselective a1A antagonist, Abbott-232. Changes in the degree of crystallinity as a result of compression and milling have also been widely reported.17–21 Hence, it makes much sense, to include the role of secondary manufacturing in the solid form screening step at the early stage of preformulation. The need for more refined polymorph screens has been recognized;22,23 however, no practical solution has been proposed so far. This study demonstrates an approach for expanding traditional solid form screening technology with the process-induced stresses encountered during secondary manufacturing. The prototype unit, denoted CryProc (Crystallization-Processing), combines wellplate-based crystallizations with miniaturized smallscale processing equipment, mimicking wet massing, JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
drying, milling, and compaction operations. The model compounds theophylline and nifedipine are subjected to screening.
MATERIALS AND METHODS Materials Theophylline anhydrate and monohydrate were obtained from BASF (Ludwigshafen, Germany) and Nomeco (Copenhagen, Denmark), respectively. Nifedepine (stable a form) was purchased from Hawkins Pharmaceutical Group (Minneapolis, MN). The chemical structures of theophylline and nifedipine are shown in Figure 1. The solid form of theophylline (anhydrate and monohydrate) and nifedipine was verified by Raman spectroscopy (see below) using the reference spectra provided by Jørgensen et al.14 and Chan et al.,24 respectively. In addition, the differentiation between anhydrate and monohydrate forms of theophylline was supported by near-infrared (NIR) spectroscopy (see below).
Methods The Crystallization-Processing (CryProc) Unit CryProc, carrying a 2 2 well-plate system, is presented in Figure 2. The well-plate chassis is made out of aluminum to ensure fast heat transfer, while the vials and small-scale processing equipment are constructed of stainless steel in order to sustain shear forces. Active heating/cooling of the vials was performed using a circulating water bath (Ecoline RE106; Lauda Brinkmann, Westbury, NY) with attached thermostat (Ecoline E100; Lauda Brinkmann). The temperature of the primary well-plate unit was monitored using a thermocouple (ama-digit ad 15th, Germany) inserted into the center of the unit.
Figure 1. Chemical structures of theophylline and nifedipine. DOI 10.1002/jps
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Figure 2. The various elements of CryProc used for expanded solid form screening. The 2 2 well-plate chassis shown on the left-hand side includes four vials.
The basic principle of the modular CryProc unit is that we can easily expand it to the desired size. Small-Scale Crystallizations (Theophylline) The possibility to perform solvent-based crystallizations was demonstrated by theophylline anhydrate from four solvents: acetonitrile, acetic acid, water, and methanol. A suitable amount of sample powder—according to the solubility in a specific solvent—was transferred to each of the four vials: 2.50 mL of each solvent was separately added to a vial. The slurries were then heated to approximately 608C until dissolved (approximately heating rate 58C/min), followed by natural cooling to ambient temperature. Acetonitrile, acetic acid, and methanol were evaporated after cooling whereas water was removed by filtering. The solid state of the recrystallized yield (<100 mg) from each of the four vials was investigated by Raman spectroscopy. Small-Scale Processing Wet Massing (Theophylline). One gram of theophylline anhydrate was transferred to a single vial. The solid form of the starting material was verified by Raman and NIR spectroscopy. The wet massing device was attached to a power drill (Type SB.25, Holstebro Jernstøberi & Maskinfabrik, Holstebro, Denmark) and stirring of the sample powder was commenced at 1290 rpm. Immediately thereafter and during stirring, a single drop (approximately 50 mL) of distilled water was added using a Pasteur pipette. Wet massing time was 2 min. The existence of agglomerated particles was visually observed. DOI 10.1002/jps
Drying (Theophylline). Fifty milligrams of theophylline monohydrate was transferred to a vial and kept at 608C for 50 min. The temperature in the center of the prototype unit was continuously monitored and kept at 60 18C. The solid state was monitored every 30 s using Raman and NIR spectroscopy until reaching the end point after 50 min. Milling (Nifedipine). Amorphous nifedipine was prepared by melting a-nifedipine at approximately 1858C and then quenching the melt on the ice. Thirty milligrams of amorphous nifedipine was transferred to a single vial. Three balls (see Fig. 2), corresponding to a ball to mass ratio of 50:1, were added to the vial. The mass of the three balls is 1.5 g, and the diameter of each ball is 5 mm. The vial was sealed shut with a lid. Small-scale ball milling was simulated by shaking the vial on a vortex mixer (Type vv3; VWR International, West Chester, PA) at approximately 2500 shakes/min (speed 4.5). Milling was performed at room temperature (19 18C), and no significant temperature increase was detected at the end of the milling (20 min). A very small amount of sample (approximately 1 mg) was taken for Raman analysis at several predetermined time intervals during the milling. All experiments of nifedipine were carried out in the dark, and no chemical degradation of nifedipine was observed after milling. Compaction (Nifedipine). Two hundred milligrams of amorphous nifedipine was compressed directly in a single vial using the punch shown in Figure 2 and a manual hydraulic press (PerkinElmer, Germany). The applied pressure was approximately 100 MPa. The solid state at the end point was analyzed by Raman spectroscopy (see below). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
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Solid-State Analysis Near-Infrared Spectroscopy (NIR). The diffuse reflectance NIR spectra of theophylline samples were recorded using a dispersive spectrometer (Control Development, Inc., South Bend, IN) with a fiber optic probe, a tungsten light source, and a thermoelectrically cooled InGaAs diode array detector. Each NIR spectrum was the average of 32 consecutive scans with a 10-ms integration time and a point resolution of 8 cm1. The use of fiber optics made it possible to measure directly in the vial. Raman Spectroscopy. Theophylline samples were measured using a dispersive Raman spectrometer with a fiber optic probe (laser spot size 90 mm, focal length 5 mm; InPhotonics, Norwood, MA), a diode laser (wavelength 785 nm; Starbright 785 S, Torsana Laser Technologies, Skodsborg, Denmark) and a thermoelectrically cooled 2DMPP charge coupled device (CCD) (1024 64) detector (Control Development, Inc.). Each spectrum was the average of eight consecutive scans with a 4-s integration time and a point resolution of 3 cm1. The use of fiber optics made it possible to measure directly in the vial. Nifedipine samples were measured using a Renishaw Ramascope System 1000 with a NIR diode laser (l ¼ 785 nm). The sample was placed on a microscopy slide and viewed under an optical Raman microscope through a 50 objective (spot size of approximately 8 mm 39 mm). A Rencam CCD silicon detector was used to acquire Raman shifts. The exposure time for data collection was set at 10 s and two accumulations per sample with a laser power of 100 mW. Wire V.2.0 software was used for instrument control and data acquisition.
lowed by dehydration upon drying at 608C. Both NIR and Raman (Fig. 3A and B, respectively) confirmed the transition of the anhydrate form into the monohydrate after 2 min of wet massing. These results are consistent with studies performed on a larger scale, which all confirm the high tendency of anhydrous theophylline to undergo hydrate formation during wet granulation.14,15 Following the wet massing step, heating at 608C for 50 min was carried out, resulting in dehydration of theophylline monohydrate (Fig. 3A and B, bottom). No formation of a
RESULTS AND DISCUSSION Small-Scale Crystallizations (Theophylline) Raman spectroscopy confirmed the generation of the monohydrate form when recrystallizing from water, while the use of the remaining solvents resulted in the stable low-temperature anhydrate form (results not shown). Thus, a metallic crystallization unit, sustainable to high mechanical stress, may be used as an alternative to the traditional well-plate systems. No more emphasis will be put on this, as the ability to perform small-scale solvent-based crystallizations has been reported elsewhere.8–10,25,26
Small-Scale Wet Massing and Drying (Theophylline) Small-scale wet massing of theophylline resulted in an anhydrate-to-monohydrate transformation, folJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
Figure 3. (A) SNV-corrected NIR spectra collected from the wet massing and drying studies measured at the end points. Theophylline anhydrate was used as starting material in the wet massing experiment, while the monohydrate was exposed to drying. (B) SNV-corrected Raman spectra collected from the wet massing and drying studies measured at the end points. Theophylline anhydrate was used as starting material in the wet massing experiment, while the monohydrate was exposed to drying. DOI 10.1002/jps
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metastable theophylline polymorph was observed under these conditions. This is not entirely unexpected as the generation of metastable theophylline is favored only at drying temperatures below 608C; above this temperature, fast transformation into the stable anhydrate form takes place.11,27 The possibility for (unexpected) formation of a hydrate during processing is an important issue to address. If no or only partial dehydration occurs in the subsequent drying phase, there is a risk of water removal during storage of the final product. In addition, dehydration kinetics can be very complex, sometimes resulting in an end product comprised of multiple solid forms. For example, three different solid forms of carbamazepine, including amorphous material, were detected at the end point of isothermal fluidized bed drying.28 Ultimately this can severely affect product performance. Thus, knowledge on the sensitivity of the API solid form towards shear forces, increased water activity, and elevated temperatures is indeed essential information, which should be available at an early stage of drug development.
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detected transiently upon heating to the temperatures above its glass transition temperature (488C). Because the milling temperature was maintained at room temperature (19 18C) in this study, it is not unexpected that not all the intermediate polymorphs of nifedipine were found. In terms of compaction, the solid form of the compact was verified as the stable a form exclusively, thus underpinning the poor physical stability of amorphous nifedipine towards high pressures. Unit operations such as milling for particle size reduction and compression represent essential parts of solid dosage form development. Phase changes taking place during these steps are usually undesirable and should therefore be thoroughly understood prior to actual manufacturing. As for the wet massing and drying steps, it seems rational to include the stresses associated with milling and tableting in solid form screening activities performed during preformulation.
Implications for Preformulation and Manufacturing Small-Scale Milling and Compaction (Nifedipine) In this part, the physical stability of amorphous nifedipine towards mechanical activation was investigated. With respect to ball milling, solid-state analysis was performed at predetermined time points in order to screen for possible solid form intermediates. From Figure 4 it is readily apparent that amorphous nifedipine starts transforming to the metastable b form after approximately 4 min of milling. This is seen as the occurrence of a small peak at approximately 1680 cm1, attributed to C – O stretching vibration, and the shift and sharpening of the peak at approximately 1350 cm1 (NO2 stretch) in b-nifedipine,24 the latter confirming an increase in the degree of long-range order (compared to the amorphous reference spectrum).29 Upon continued milling, there is a gradual conversion of metastable nifedipine into the stable a form. Finally, after 20 min of milling the presence of a-nifedipine is more pronounced. Chan et al.24 reported that bnifedipine can be produced by grinding crushed amorphous nifedipine in a Specamill agate vibrating mill. This is consistent with our finding that smallscale milling can induce the devitrification of amorphous nifedipine. Also, a number of researchers have suggested the existence of a third polymorph, gnifedipine, during the devitrification of amorphous nifedipine,30–32 while Keymolen et al.33 recently reported a fourth polymorph of nifedipine. However, in all these studies, the devitrification of amorphous nifedipine was caused by an increased temperature, where the three intermediate polymorphs were DOI 10.1002/jps
According to McCrone, every compound has different polymorphic forms, and the number of forms known for a given compound is proportional to the time and money invested in research on that particular compound.1 However, as is the case during preformulation (and drug development in general) there is only a limited time available for carrying out the screening, and consequently the researcher must construct a screening design that provides rapid, yet valuable, API solid-state information. Therefore, a judiciously designed solid form screening is the key to successful preformulation work and ultimately the development of a robust drug formulation. The solid form screening platform, CryProc, reported here, expands the commonly used wellplate-based crystallizations with stresses encountered during manufacturing. These stresses are simulated using miniaturized processing equipment in order to meet the requirements of a low API consumption. It presents a rational and science-based approach to solid form screening that takes into account the significant amounts of energy introduced by commonly used unit operations. Based on the model compounds theophylline and nifedipine, phase changes were observed during all four simulated manufacturing steps: wet massing, drying, milling, and compaction. This kind of expanded screening design provides several advantages. Firstly, the application of stresses not used in traditional screening increases the probability of finding all relevant solid forms of a lead candidate. Secondly, early insight into the role of secondary manufacturing enables the identification of high-risk unit operations, thus JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
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Figure 4. Raman raw spectra collected from the milling and compaction studies. Amorphous nifedipine was used as starting material for both types of unit operations. The milling length and the polymorphs induced by milling at each time point were indicated.
providing knowledge support for choosing the right processing equipment. This is of particular importance when metastable or amorphous forms are selected for further development. Finally, as the platform operates from a high-throughput perspective—that is, crystallizations and small-scale processing can in principle be fully automated—the overall screening is performed rapidly and with minimal API consumption. Future studies will focus on more comprehensive screening designs (using a refined second-generation prototype and kinetic profiling), including more test compounds and process variables at several levels. The addition of excipients would further add value to the screening output, since excipients are well known JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
to be able to affect the solid-state transition kinetics of APIs during various unit operations. Also, solid-state changes of an excipient in a formulation may have major impact on the overall product quality.34 It would thus seem rational to include the role of relevant excipients when screening the API in question.
CONCLUSIONS Solid form screening is an essential part of all drug development programs. The screening is designed to find as many forms as possible and, further, to identify the most suitable form for development. DOI 10.1002/jps
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However, less attention is paid to the role of secondary manufacturing, during which PITs of the API may occur. There is a potential risk that these solid-state changes are retained in the final solid dosage form, which may ultimately affect product quality. In this study, a new tool for effective solid form screening was proposed and demonstrated. The CryProc technology combines traditional well-platebased crystallizations of the API with the evaluation of the role of secondary manufacturing. This is made possible through the use of miniaturized processing equipment applied directly to the well-plate system. In the current prototype, unit operations include wet massing, drying, milling, and compaction. Besides increasing the possibility of finding all API solid forms, this kind of expanded screening also provides increased process understanding at an early stage of drug development and, furthermore, can be used as decision-making tool when choosing the most suitable routes of manufacture for the API in question.
ACKNOWLEDGMENTS We acknowledge Lasse Johansson from Technical Support at the Faculty of Pharmaceutical Sciences for his aid in the engineering of CryProc. The Renishaw Raman microscope was used with permission from Erik Skibsted, Novo Nordisk A/S, to whom we are thankful.
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¨ , Hickey MB, Peterson ML, Morissette SL, Sou8. Almarsson O kasene S, McNulty C, Tawa M, MacPhee JM, Remenar JF. 2003. High-throughput surveys of crystal form diversity of highly polymorphic pharmaceutical compounds. Cryst Growth Des 3:927–933. 9. Morissette SL, Soukasene S, Levinson D, Cima MJ, Almarsson ¨ . 2003. Elucidation of crystal form diversity of the HIV O protease inhibitor ritonavir by high-throughput crystallization. Proc Natl Acad Sci USA 100:2180–2184. 10. Peterson ML, Morissette SL, McNulty C, Goldsweig A, Shaw P, LeQuesne M, Monagle J, Encina N, Marchionna J, Johnson A, Gonzalez-Zugasti J, Lemmo AV, Ellis SJ, Cima MJ, Almarsson ¨ . 2002. Iterative high-throughput polymorphism studies on O acetaminophen and an experimentally derived structure for form III. J Am Chem Soc 124:10958–10959. 11. Morris KR, Griesser UJ, Eckhardt CJ, Stowell JG. 2001. Theoretical approaches to physical transformations of active pharmaceutical ingredients during manufacturing processes. Adv Drug Deliv Rev 48:91–114. 12. Zhang GGZ, Law D, Schmitt EA, Qiu YH. 2004. Phase transformation considerations during process development and manufacture of solid oral dosage forms. Adv Drug Deliv Rev 56:371–390. 13. Bauer-Brandl A. 1996. Polymorphic transitions of cimetidine during manufacture of solid dosage forms. Int J Pharm 140: 195–206. 14. Jørgensen A, Rantanen J, Karjalainen M, Khriachtchev L, Ra¨ sa¨ nen E, Yliruusi J. 2002. Hydrate formation during wet granulation studied by spectroscopic methods and multivariate analysis. Pharm Res 19:1285–1291. 15. Wikstro¨ m H, Marsac PJ, Taylor LS. 2004. In-line monitoring of hydrate formation during wet granulation using Raman spectroscopy. J Pharm Sci 94: 209–219. 16. Wardrop J, Law D, Qiu Y, Engh K, Faitsch L, Ling C. 2006. Influence of solid phase and formulation processing on stability of Abbott-232 tablet formulations. J Pharm Sci 95:2380–2392. 17. Brittain HG. 2002. Effects of mechanical processing on phase composition. J Pharm Sci 91:1573–1580. 18. Ghan GA, Lalla JK. 1992. Effect of compressional forces on piroxicam polymorphs. J Pharm Pharmacol 44:678–681. 19. Okumura T, Ishida M, Takayama K, Otsuka M. 2006. Polymorphic transformation of indomethacin under high pressures. J Pharm Sci 95:689–700. 20. Pirttima¨ ki J, Laine E, Ketolainen J, Paronen P. 1993. Effects of grinding and compression on crystal-structure of anhydrous caffeine. Int J Pharm 95:93–99. 21. Shakhtshneider TP, Boldyrev VV. 1993. Phase-transformations in sulfathiazole during mechanical activation. Drug Dev Ind Pharm 19:2055–2067. 22. Chow K, Tong HH, Lum S, Chow AH. 2007. Engineering of pharmaceutical materials: An industrial perspective. J Pharm Sci 97:2855–2877. 23. Grant DJ, Byrn SR. 2004. A timely re-examination of drug polymorphism in pharmaceutical development and regulation. Adv Drug Deliv Rev 56:237–239. 24. Chan KLA, Fleming OS, Kazarian SG, Vassou D, Chryssikos GD, Gionis V. 2004. Polymorphism and devitrification of nifedipine under controlled humidity: A combined FT-Raman, IR and Raman microscopic investigation. J Raman Spectrosc 35: 353–359. 25. Storey R, Docherty R, Higginson P, Dallman C, Gilmore C, Barr G, Dong W. 2004. Automation of solid form screening procedures in the pharmaceutical industry—How to avoid the bottlenecks. Crystallogr Rev 10:45–56. 26. Hilfiker R, Berghausen J, Blatter F, Burkhard A, De Paul SM, Freiermuth B, Geoffroy A, Hofmeier U, Marcolli C, Siebenhaar B, Szelagiewicz M, Vit A, von Raumer M. 2003. Polymorphism—Integrated approach from high-throughput screening to JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
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31. Grooff D, De Villiers MM, Liebenberg W. 2007. Thermal methods for evaluating polymorphic transitions in nifedipine. Thermochim Acta 454: 33–42. 32. Hirayama F, Wang Z, Uekama K. 1994. Effect of 2-hydroxypropyl-beta-cyclodextrin on crystallization and polymorphic transition of nifedipine in solid-state. Pharm Res 11:1766– 1770. 33. Keymolen B, Ford JL, Powell MW, Rajabi-Siahboomi AR. 2003. Investigation of the polymorphic transformations from glassy nifedipine. Thermochim Acta 397:103–117. 34. Govindarajan R, Suryanarayanan R. 2006. Processing-induced phase transformations and their implications on pharmaceutical product quality. In: Hilfiker R, editor. Polymorphism in the pharmaceutical industry. Weinheim: Wiley-VCH. pp. 333– 364.
DOI 10.1002/jps
Keywords: polymorph screening; hydrate; amorphous; process-induced transformations (PITs); high throughput; near-infrared (NIR) spectroscopy; Raman spectroscopy; theophylline; nifedipine
INTRODUCTION Polymorphism, that is, the ability of a solid to exist in more than one crystal structure,1 is an area of great interest and concern to the pharmaceutical industry. The reasons for this are related to (1) product quality and performance, as polymorphs often show varying dissolution behavior, stability, and processability, and (2) financial aspects, since each polymorph is patentable.2 Solids may also exist as amorphous material with no long-range order. Likewise, the active pharmaceutical ingredient (API) molecule may coexist with a guest molecule. The crystal forms are designated a solvate or a cocrystal, when the guest molecule is a liquid or solid at room temperature, respectively. Salts are distinguished from all other forms by being stabilized by ionic bonding between API and guest molecule. To avoid term confusion, all above-mentioned solid modifications (i.e., polymorphs, amorphous material, solvates, cocrystals) Correspondence to: Jukka Rantanen (Telephone: þ45-35336000; Fax: þ45-35336030; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 99, 3711–3718 (2010) ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association
are henceforth referred to as solid forms. It is crucial to perform a thorough and reliable solid form screening at the early stage of preformulation. The objective of this screening is to find as many solid forms as possible and to identify the most suitable form for further development.3 In most cases the stable form is desired, though a need for enhanced dissolution rate may sometimes lead to the manufacture of a metastable crystalline form or amorphous material.4 However, no matter how thorough a screening, the burning question still remains: Has the most stable form actually been found? This is often not possible to answer with absolute confidence, as metastable forms may remain in their structural arrangement for a relatively long time. A startling example of an appearing new polymorphic form is the case of ritonavir, a peptidomimetic drug used to treat HIV-1 infection and introduced in 1996 (Norvir, Abbott Laboratories, Chicago, IL).5 During development and initial manufacture of ritonavir, only one monoclinic crystal form was known. In 1998, a lower energy, more stable form (form II) appeared, causing slower dissolution. Two years after entry into the market, several lots of Norvir capsules began failing dissolution specifications. Evaluation of the failed
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drug products revealed that a second and more stable crystal form of ritonavir (form II) had precipitated from the formulation. At some considerable cost a new formulation of Norvir was eventually developed and launched. This illustrates the importance of conducting a well-designed and thorough screening, properly spanning the multiparameter space that contributes to API solid form diversity. There is no specific methodology available for performing polymorph screening.6 This is mostly due to the poor understanding of nucleation and crystal growth phenomena, which underlines the need for experimental approaches in this field. The use of automated highthroughput technology has become widely popular.7 The main advantage of high-throughput systems lies in the large number of crystallizations carried out (several hundreds in a single run), which in addition utilize low API quantities and little if no manual intervention. This allows for large experimental designs where several factors are varied, including heating rate, cooling rate, degree of supersaturation, solvent type, etc. However, poor API solubility in some solvents often results in low hit rates for these systems (between 2.5% and 13%).8–10 Manual benchscale crystallizations are used to solve the issue of low solubility, utilizing larger solvent volumes and thus more API. However, current high-throughput as well as bench-scale technology suffer from one major drawback: They do not take into account the impact of secondary manufacturing on API polymorphism. Stresses encountered during manufacturing are well known to be able to cause process-induced transformations (PITs) of the initial API solid form which ultimately may lead to altered product attributes.11– 13 During pharmaceutical unit operations, processinduced stresses originate from temperature (e.g., drying phase), mechanical activation (e.g., milling, compression), or water/solvate (e.g., wet granulation). The anhydrate-to-hydrate conversion of theophylline during wet granulation has been reported,14,15 while Wardrop et al.16 observed an anhydrate-to-amorphous conversion of the uroselective a1A antagonist, Abbott-232. Changes in the degree of crystallinity as a result of compression and milling have also been widely reported.17–21 Hence, it makes much sense, to include the role of secondary manufacturing in the solid form screening step at the early stage of preformulation. The need for more refined polymorph screens has been recognized;22,23 however, no practical solution has been proposed so far. This study demonstrates an approach for expanding traditional solid form screening technology with the process-induced stresses encountered during secondary manufacturing. The prototype unit, denoted CryProc (Crystallization-Processing), combines wellplate-based crystallizations with miniaturized smallscale processing equipment, mimicking wet massing, JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
drying, milling, and compaction operations. The model compounds theophylline and nifedipine are subjected to screening.
MATERIALS AND METHODS Materials Theophylline anhydrate and monohydrate were obtained from BASF (Ludwigshafen, Germany) and Nomeco (Copenhagen, Denmark), respectively. Nifedepine (stable a form) was purchased from Hawkins Pharmaceutical Group (Minneapolis, MN). The chemical structures of theophylline and nifedipine are shown in Figure 1. The solid form of theophylline (anhydrate and monohydrate) and nifedipine was verified by Raman spectroscopy (see below) using the reference spectra provided by Jørgensen et al.14 and Chan et al.,24 respectively. In addition, the differentiation between anhydrate and monohydrate forms of theophylline was supported by near-infrared (NIR) spectroscopy (see below).
Methods The Crystallization-Processing (CryProc) Unit CryProc, carrying a 2 2 well-plate system, is presented in Figure 2. The well-plate chassis is made out of aluminum to ensure fast heat transfer, while the vials and small-scale processing equipment are constructed of stainless steel in order to sustain shear forces. Active heating/cooling of the vials was performed using a circulating water bath (Ecoline RE106; Lauda Brinkmann, Westbury, NY) with attached thermostat (Ecoline E100; Lauda Brinkmann). The temperature of the primary well-plate unit was monitored using a thermocouple (ama-digit ad 15th, Germany) inserted into the center of the unit.
Figure 1. Chemical structures of theophylline and nifedipine. DOI 10.1002/jps
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Figure 2. The various elements of CryProc used for expanded solid form screening. The 2 2 well-plate chassis shown on the left-hand side includes four vials.
The basic principle of the modular CryProc unit is that we can easily expand it to the desired size. Small-Scale Crystallizations (Theophylline) The possibility to perform solvent-based crystallizations was demonstrated by theophylline anhydrate from four solvents: acetonitrile, acetic acid, water, and methanol. A suitable amount of sample powder—according to the solubility in a specific solvent—was transferred to each of the four vials: 2.50 mL of each solvent was separately added to a vial. The slurries were then heated to approximately 608C until dissolved (approximately heating rate 58C/min), followed by natural cooling to ambient temperature. Acetonitrile, acetic acid, and methanol were evaporated after cooling whereas water was removed by filtering. The solid state of the recrystallized yield (<100 mg) from each of the four vials was investigated by Raman spectroscopy. Small-Scale Processing Wet Massing (Theophylline). One gram of theophylline anhydrate was transferred to a single vial. The solid form of the starting material was verified by Raman and NIR spectroscopy. The wet massing device was attached to a power drill (Type SB.25, Holstebro Jernstøberi & Maskinfabrik, Holstebro, Denmark) and stirring of the sample powder was commenced at 1290 rpm. Immediately thereafter and during stirring, a single drop (approximately 50 mL) of distilled water was added using a Pasteur pipette. Wet massing time was 2 min. The existence of agglomerated particles was visually observed. DOI 10.1002/jps
Drying (Theophylline). Fifty milligrams of theophylline monohydrate was transferred to a vial and kept at 608C for 50 min. The temperature in the center of the prototype unit was continuously monitored and kept at 60 18C. The solid state was monitored every 30 s using Raman and NIR spectroscopy until reaching the end point after 50 min. Milling (Nifedipine). Amorphous nifedipine was prepared by melting a-nifedipine at approximately 1858C and then quenching the melt on the ice. Thirty milligrams of amorphous nifedipine was transferred to a single vial. Three balls (see Fig. 2), corresponding to a ball to mass ratio of 50:1, were added to the vial. The mass of the three balls is 1.5 g, and the diameter of each ball is 5 mm. The vial was sealed shut with a lid. Small-scale ball milling was simulated by shaking the vial on a vortex mixer (Type vv3; VWR International, West Chester, PA) at approximately 2500 shakes/min (speed 4.5). Milling was performed at room temperature (19 18C), and no significant temperature increase was detected at the end of the milling (20 min). A very small amount of sample (approximately 1 mg) was taken for Raman analysis at several predetermined time intervals during the milling. All experiments of nifedipine were carried out in the dark, and no chemical degradation of nifedipine was observed after milling. Compaction (Nifedipine). Two hundred milligrams of amorphous nifedipine was compressed directly in a single vial using the punch shown in Figure 2 and a manual hydraulic press (PerkinElmer, Germany). The applied pressure was approximately 100 MPa. The solid state at the end point was analyzed by Raman spectroscopy (see below). JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
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Solid-State Analysis Near-Infrared Spectroscopy (NIR). The diffuse reflectance NIR spectra of theophylline samples were recorded using a dispersive spectrometer (Control Development, Inc., South Bend, IN) with a fiber optic probe, a tungsten light source, and a thermoelectrically cooled InGaAs diode array detector. Each NIR spectrum was the average of 32 consecutive scans with a 10-ms integration time and a point resolution of 8 cm1. The use of fiber optics made it possible to measure directly in the vial. Raman Spectroscopy. Theophylline samples were measured using a dispersive Raman spectrometer with a fiber optic probe (laser spot size 90 mm, focal length 5 mm; InPhotonics, Norwood, MA), a diode laser (wavelength 785 nm; Starbright 785 S, Torsana Laser Technologies, Skodsborg, Denmark) and a thermoelectrically cooled 2DMPP charge coupled device (CCD) (1024 64) detector (Control Development, Inc.). Each spectrum was the average of eight consecutive scans with a 4-s integration time and a point resolution of 3 cm1. The use of fiber optics made it possible to measure directly in the vial. Nifedipine samples were measured using a Renishaw Ramascope System 1000 with a NIR diode laser (l ¼ 785 nm). The sample was placed on a microscopy slide and viewed under an optical Raman microscope through a 50 objective (spot size of approximately 8 mm 39 mm). A Rencam CCD silicon detector was used to acquire Raman shifts. The exposure time for data collection was set at 10 s and two accumulations per sample with a laser power of 100 mW. Wire V.2.0 software was used for instrument control and data acquisition.
lowed by dehydration upon drying at 608C. Both NIR and Raman (Fig. 3A and B, respectively) confirmed the transition of the anhydrate form into the monohydrate after 2 min of wet massing. These results are consistent with studies performed on a larger scale, which all confirm the high tendency of anhydrous theophylline to undergo hydrate formation during wet granulation.14,15 Following the wet massing step, heating at 608C for 50 min was carried out, resulting in dehydration of theophylline monohydrate (Fig. 3A and B, bottom). No formation of a
RESULTS AND DISCUSSION Small-Scale Crystallizations (Theophylline) Raman spectroscopy confirmed the generation of the monohydrate form when recrystallizing from water, while the use of the remaining solvents resulted in the stable low-temperature anhydrate form (results not shown). Thus, a metallic crystallization unit, sustainable to high mechanical stress, may be used as an alternative to the traditional well-plate systems. No more emphasis will be put on this, as the ability to perform small-scale solvent-based crystallizations has been reported elsewhere.8–10,25,26
Small-Scale Wet Massing and Drying (Theophylline) Small-scale wet massing of theophylline resulted in an anhydrate-to-monohydrate transformation, folJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
Figure 3. (A) SNV-corrected NIR spectra collected from the wet massing and drying studies measured at the end points. Theophylline anhydrate was used as starting material in the wet massing experiment, while the monohydrate was exposed to drying. (B) SNV-corrected Raman spectra collected from the wet massing and drying studies measured at the end points. Theophylline anhydrate was used as starting material in the wet massing experiment, while the monohydrate was exposed to drying. DOI 10.1002/jps
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metastable theophylline polymorph was observed under these conditions. This is not entirely unexpected as the generation of metastable theophylline is favored only at drying temperatures below 608C; above this temperature, fast transformation into the stable anhydrate form takes place.11,27 The possibility for (unexpected) formation of a hydrate during processing is an important issue to address. If no or only partial dehydration occurs in the subsequent drying phase, there is a risk of water removal during storage of the final product. In addition, dehydration kinetics can be very complex, sometimes resulting in an end product comprised of multiple solid forms. For example, three different solid forms of carbamazepine, including amorphous material, were detected at the end point of isothermal fluidized bed drying.28 Ultimately this can severely affect product performance. Thus, knowledge on the sensitivity of the API solid form towards shear forces, increased water activity, and elevated temperatures is indeed essential information, which should be available at an early stage of drug development.
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detected transiently upon heating to the temperatures above its glass transition temperature (488C). Because the milling temperature was maintained at room temperature (19 18C) in this study, it is not unexpected that not all the intermediate polymorphs of nifedipine were found. In terms of compaction, the solid form of the compact was verified as the stable a form exclusively, thus underpinning the poor physical stability of amorphous nifedipine towards high pressures. Unit operations such as milling for particle size reduction and compression represent essential parts of solid dosage form development. Phase changes taking place during these steps are usually undesirable and should therefore be thoroughly understood prior to actual manufacturing. As for the wet massing and drying steps, it seems rational to include the stresses associated with milling and tableting in solid form screening activities performed during preformulation.
Implications for Preformulation and Manufacturing Small-Scale Milling and Compaction (Nifedipine) In this part, the physical stability of amorphous nifedipine towards mechanical activation was investigated. With respect to ball milling, solid-state analysis was performed at predetermined time points in order to screen for possible solid form intermediates. From Figure 4 it is readily apparent that amorphous nifedipine starts transforming to the metastable b form after approximately 4 min of milling. This is seen as the occurrence of a small peak at approximately 1680 cm1, attributed to C – O stretching vibration, and the shift and sharpening of the peak at approximately 1350 cm1 (NO2 stretch) in b-nifedipine,24 the latter confirming an increase in the degree of long-range order (compared to the amorphous reference spectrum).29 Upon continued milling, there is a gradual conversion of metastable nifedipine into the stable a form. Finally, after 20 min of milling the presence of a-nifedipine is more pronounced. Chan et al.24 reported that bnifedipine can be produced by grinding crushed amorphous nifedipine in a Specamill agate vibrating mill. This is consistent with our finding that smallscale milling can induce the devitrification of amorphous nifedipine. Also, a number of researchers have suggested the existence of a third polymorph, gnifedipine, during the devitrification of amorphous nifedipine,30–32 while Keymolen et al.33 recently reported a fourth polymorph of nifedipine. However, in all these studies, the devitrification of amorphous nifedipine was caused by an increased temperature, where the three intermediate polymorphs were DOI 10.1002/jps
According to McCrone, every compound has different polymorphic forms, and the number of forms known for a given compound is proportional to the time and money invested in research on that particular compound.1 However, as is the case during preformulation (and drug development in general) there is only a limited time available for carrying out the screening, and consequently the researcher must construct a screening design that provides rapid, yet valuable, API solid-state information. Therefore, a judiciously designed solid form screening is the key to successful preformulation work and ultimately the development of a robust drug formulation. The solid form screening platform, CryProc, reported here, expands the commonly used wellplate-based crystallizations with stresses encountered during manufacturing. These stresses are simulated using miniaturized processing equipment in order to meet the requirements of a low API consumption. It presents a rational and science-based approach to solid form screening that takes into account the significant amounts of energy introduced by commonly used unit operations. Based on the model compounds theophylline and nifedipine, phase changes were observed during all four simulated manufacturing steps: wet massing, drying, milling, and compaction. This kind of expanded screening design provides several advantages. Firstly, the application of stresses not used in traditional screening increases the probability of finding all relevant solid forms of a lead candidate. Secondly, early insight into the role of secondary manufacturing enables the identification of high-risk unit operations, thus JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
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Figure 4. Raman raw spectra collected from the milling and compaction studies. Amorphous nifedipine was used as starting material for both types of unit operations. The milling length and the polymorphs induced by milling at each time point were indicated.
providing knowledge support for choosing the right processing equipment. This is of particular importance when metastable or amorphous forms are selected for further development. Finally, as the platform operates from a high-throughput perspective—that is, crystallizations and small-scale processing can in principle be fully automated—the overall screening is performed rapidly and with minimal API consumption. Future studies will focus on more comprehensive screening designs (using a refined second-generation prototype and kinetic profiling), including more test compounds and process variables at several levels. The addition of excipients would further add value to the screening output, since excipients are well known JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 99, NO. 9, SEPTEMBER 2010
to be able to affect the solid-state transition kinetics of APIs during various unit operations. Also, solid-state changes of an excipient in a formulation may have major impact on the overall product quality.34 It would thus seem rational to include the role of relevant excipients when screening the API in question.
CONCLUSIONS Solid form screening is an essential part of all drug development programs. The screening is designed to find as many forms as possible and, further, to identify the most suitable form for development. DOI 10.1002/jps
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However, less attention is paid to the role of secondary manufacturing, during which PITs of the API may occur. There is a potential risk that these solid-state changes are retained in the final solid dosage form, which may ultimately affect product quality. In this study, a new tool for effective solid form screening was proposed and demonstrated. The CryProc technology combines traditional well-platebased crystallizations of the API with the evaluation of the role of secondary manufacturing. This is made possible through the use of miniaturized processing equipment applied directly to the well-plate system. In the current prototype, unit operations include wet massing, drying, milling, and compaction. Besides increasing the possibility of finding all API solid forms, this kind of expanded screening also provides increased process understanding at an early stage of drug development and, furthermore, can be used as decision-making tool when choosing the most suitable routes of manufacture for the API in question.
ACKNOWLEDGMENTS We acknowledge Lasse Johansson from Technical Support at the Faculty of Pharmaceutical Sciences for his aid in the engineering of CryProc. The Renishaw Raman microscope was used with permission from Erik Skibsted, Novo Nordisk A/S, to whom we are thankful.
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DOI 10.1002/jps