Pentamorphs of Acedapsone - ACS Publications - American Chemical

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Pentamorphs of Acedapsone Geetha Bolla, Sudhir Mittapalli, and Ashwini Nangia* School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Central University P.O., Hyderabad 500 046, India S Supporting Information *

ABSTRACT: Acedapsone is a long acting prodrug of Dapsone, the diacetyl derivative of diaminophenyl sulfone. It exhibits superior bioavailability compared to the parent drug. Dapsone occupies a preeminent position in the treatment of leprosy since the 1940s. Surprisingly no X-ray crystal structure or polymorphs of acedapsone are reported. Five novel polymorphs of acedapsone are reported (I−V) of which crystal forms I and II are characterized by single X-ray diffraction. These novel polymorphs were crystallized from solution, slow cooling of the melt, and spray-drying of the powder. Solution crystallization afforded Acedapsone Forms I and II. Slow cooling of the melt phase resulted in an amorphous phase, which transformed to a new Form IV slowly at room temperature, and then to Form III. Fast cooling or quick quench of the amorphous solid gave Form I. Spray drying resulted in a new metastable polymorph V, but this polymorph also converted to Form III at room temperature after 6 h. In addition to five crystalline polymorphs of acedapsone, an amorphous phase was also obtained from the melt. XPac analysis of polymorphs I and II (space group P21/n and C2/c) showed 2D isostructurality, and Hirshfeld surface analysis revealed subtle differences in the molecular environment of the two crystal structures. The stability of five polymorphs by DSC, VT-PXRD, and upon heating in a sealed tube suggested that the kinetic stability order is Form I (most stable) > II > III > IV > V > amorphous (least stable), whereas competitive slurry and liquidassisted grinding experiments gave the thermodynamic stability as Form II (most stable) > I > III > IV > V > amorphous (least stable). Solventless methods such as quench cooling of the melt and holding in a sealed tube at high temperature and pressure yielded the kinetically stable Form I. Spray drying of the powder gave metastable Forms III and V (which transformed over time), and slurry conditions gave the thermodynamic Form II. The pentamorphic system follows Ostwald’s law of stages. The role of solvent selection in the direct crystallization of Acedapsone polymorphs after diacetylation of Dapsone is also discussed.

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INTRODUCTION Even as several methods are used in the pharmaceutical industry to tune the physicochemical properties of active pharmaceutical ingredients (APIs) by solid form screening,1 there are still many simple and popular drugs whose polymorphic structures have not yet been systematically screened and analyzed. The formulation of drugs is preferred as oral tablets and capsules (over three-fourths of marketed drugs) for longer storage and shelf life, drug purity, patient compliance, and ease of transport and handling. Solid-state chemistry and crystal engineering offer novel approaches to study new crystalline forms of drugs.2 The attrition rates of drugs due to problems of poor physicochemical properties such as low solubility and dissolution rate, hydration, degradation, rate-limiting limited bioavailability is quite alarming (over 80% of drugs in the R&D pipeline). Optimization of the best drug form as a salt, cocrystal, polymorph, or hydrate/solvate is now practiced using rational crystal engineering strategies.3 Other approaches such as cyclodextrin complexes, solid dispersions, nano emulsions, nanosuspensions, etc., are also used, but they suffer from low active drug loading in an inert matrix for stabilization.4 Amorphous pharmaceuticals feature enhanced bioavailability but they tend to be unstable and their accidental transformation to the stable crystalline form is a down side.5 © XXXX American Chemical Society

Small particle size distribution, preparation methods, and mobility of molecules in glassy states influence the dissolution and stability of amorphous materials.6 Crystallization kinetics of the amorphous state is closely linked to molecular mobility (α,β-relaxations) of the amorphous matrix, local motions, and primarily Johari−Goldstein (JG) relaxations and the thermodynamic driving force for crystallization.7 Molecular mobility decreases by many orders of magnitude as the liquid is cooled to below its glass transition temperature which stabilizes the system. Mobility below the glass transition temperature is usually sufficient for molecules to reorient and relax to the most stable crystalline phase. Active pharmaceuticals ingredients (APIs) have been the focus of crystal engineering and pharmaceutical development groups in the past decade by making polymorphs and cocrystals to tailor the physicochemical properties.8 A polymorph is a solid crystalline phase of a given compound resulting from the possibility of at least two different arrangements of the molecules of that compound in the solid-state (McCrone, 1965).9 Molecular conformations, hydrogen bonding synthons, packing arrangements, and kinetic Received: July 11, 2014 Revised: August 25, 2014

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dx.doi.org/10.1021/cg5010424 | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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factors are important during crystal nucleation and growth.10 Hydrogen bonds and weak C−H···O interactions, halogen bonding, π···π interactions can result in multiple supramolecular synthons to give different crystal structures.11 Acedapsone (N-[4-(4-acetamidophenyl)sulfonylphenyl]acetamide), a prodrug of dapsone, is an antimicrobial drug used in the treatment of leprosy. It also exhibits antimalarial activity.12a Acedapsone (abbreviated as DADDS) is the diacetyl derivative of Dapsone (DDS, Scheme 1), which belongs to the

Acedapsone polymorphs is not reported. On the other hand, the parent drug Dapsone is relatively well studied. Caira et al.19a reported a few solvates of DDS with dichloromethane, dioxane, and THF. Cocrystals of DDS with caprolactam, 4,4′-bipyridine, 3,5-dinitrobenzoic acid, and a tosylate salt were reported to improve the physicochemical properties of dapsone.19b−d Apart from these cocrystals/salts, drug−drug cocrystals of Dapsone were recently published during the revision of this manuscript.19e We report in this paper novel solid forms of DADDS to modulate its physicochemical properties and establish their phase relations. The effect of cooling rate on melt crystallization of DADDS to give amorphous phase and new crystalline forms was studied. We show that quench cooling of molten DADDS by adding liquid nitrogen LN2 (−190 °C) gives a kinetically stable phase, Form I. Slow cooling of the same molten liquid at room temperature resulted in an amorphous phase. The amorphous material crystallized to give different metastable forms (referred to as Forms IV, III) over 3−4 days at room temperature. The behavior of these new solid forms was monitored by PXRD and DSC. Solution crystallization afforded single crystals of Forms I and II, whose structures were confirmed by X-ray diffraction. Spray drying of DADDS in MeOH gave a new Form V (confirmed by PXRD and DSC) and freeze−dryer (lyophilizer) experiments were also carried out to investigate new polymorphs.

Scheme 1. Acedapsone and Dapsone

sulfonyl aniline family of drugs. Dapsone is the first sulfone introduced by Fromm and Wittmann way back in 1908,12b but its pharmacology and therapeutic studies were not reported until 1936. Buttle et al.12c,d studied the drug in mice, rabbits, and humans for its antibacterial properties. The routine use of Dapsone as a drug started in 1943 when Faget et al.13 showed its antileprosy activity, and even today Dapsone is a mainstay in many combination drugs. It was approved by the WHO in 1977 and as a combination drug with Clofazimine and Rifampicin (WHO, 1987) for leprosy.14 According to the Biopharmaceutics Classification system (BCS), Dapsone is a Class IV drug of low solubility (10 mg/L) and low permeability (logP = 1.37).15 The major downside of DDS is low bioavailability (70−80%), and attempts to increase the drug action time were unsuccessful. Even though Acedapsone is less soluble in the aqueous medium compared to Dapsone, it exhibits higher bioavailability and protein binding.16a The metabolism of Acedapsone was studied in 15 individuals with 225 mg dose injected intramuscularly for a period of 75 days.16b The peak plasma level of dapsone after administration of Acedapsone was 85.4 ng/mL, 6 times higher compared to Dapsone (14 ng/mL). The mean concentration of Acedapsone is slightly higher than Dapsone (44.53 ng/mL compared to 41.95 ng/mL at half-life period on the 15th day). The concentration of Acedapsone on the 75th day was 14.76 ng/mL, 5 times higher than the MIC (maximum inhibitory concentration) of pure Dapsone (3 ng/ mL) against M. Leprae. The biggest advantage of DADDS is that it can be used as a long acting antileprosy drug compared to DDS with 3 times a year dose regime.16b The combination of cycloguanil pamoate with DADDS showed better activity than either of the components alone against drug-resistant plasmodia in experimental animals and in humans.17a,b The β-cyclodextrin complex (DADDS−β-CD) was shown to improve active metabolite dapsone activity.17c The importance of dapsone is well documented in the literature in terms of biological and pharmacological activity.13−15 However, no structural details of Acedapsone are available except a brief mention of two modifications visualized on Kofler’s hot stage (1978). Brandstätter, Bösch, and Eckstein18a of Inssbruck reported that a melt glassy phase of Acedapsone converts to Mod. I at 120−140 °C and then to Mod. II at 150−160 °C (modification is the same meaning as polymorph or form). A complete structural characterization of

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RESULTS AND DISCUSSION The screening of DADDS polymorphs was initiated by crystallization from solvents at room temperature (slow evaporation). Two different polymorphic modifications, named Form I and Form II, crystallized concomitantly. Under optimized conditions of crystallization, Acetone/THF afforded pure Form I whereas DMSO/DMF gave pure Form II. The X-ray crystal structures of both Forms I and II were solved and refined in the monoclinic space groups P21/c and C2/c, respectively (Z = 4, 8). Concomitant crystallization20 (the simultaneous nucleation of more than one polymorph) of polymorphs usually occurs when kinetic stabilities and nucleation rates of polymorphs under the experimental conditions are nearly the same, and in such cases kinetic factors are often more important (solvent system, rate of cooling, supersaturation, etc.). Thus, seeding and isomorphic seeding with a given polymorph in different solution crystallizations may be a preferred method to optimize conditions to obtain the desired polymorph.21 Further attempts with solution crystallization did not result in any new forms. Hence techniques such as melt cooling, spray-drying (fast solvent evaporation method), freeze−dryer, quench cool (both normal cool and rapid cool conditions), rotary evaporation technique, as well as slurry/grinding experiments were explored to isolate new polymorphs.22 An amorphous phase was obtained by heating DADDS above 300 °C and slow-cooling of the melt to room temperature. This amorphous phase was not stable at ambient conditions and rapidly transformed to a metastable crystalline Form IV over 24 h. This new Form IV itself was unstable and converted to a nearest in energy Form III, which appeared to be stable at room temperature and did not convert to Forms I or II. The method used for preparing the amorphous state and processing conditions can impact the stability of the metastable phase. Amorphous systems generated by different procedures such as milling of the crystalline phase, quench cooling, freeze−drying, spray-drying, and grinding (with and without added solvent), B



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A solvent screen to prepare DADDS polymorphs resulted in Form II at room temperature and Form I at high temperature. Crystallization conditions are detailed in the Experimental Section. Crystal Structures of DADDS. There is no X-ray crystal structure reported for DADDS with 3D coordinated determined (CSD version 2014, Feb 2014 update). Two novel polymorphs of DADDS were characterized in this study by single crystal X-ray diffraction. The concomitant polymorphs from alcoholic solvents, EtOAc, acetone solvents were separated manually by checking the unit cell of the prismatic needle (Form II) and flat plate (Form I) morphology crystals (Figure 2). The polymorphs were identified under polarized

dehydration of the sample by melting, etc., can show different physicochemical properties, notably solubility.23 For example, slow cooling of paracetamol amorphous form exhibited new metastable Form III, whereas quench cooled paracetamol crystallized as the stable Form I.24 Crystallization of a particular amorphous phase also depends on conditions such as temperature, surface area, cooling rate, and pressure.24a Apart from paracetmol, this method has been applied for a few other drugs to discover new metastable forms, e.g., Griseofulvin, Felodepine, Indomethacin, Trio-methyl-β-cyclodextrin, and Simvastatin.25 These phases were further characterized by differences in heat capacity between the supercooled liquid and the amorphous solid, which is associated with the fragility of the glass formers. Fragility is related to molecular mobility with more fragile materials having longer relaxation times below the glass transition temperature, which will affect its stability. Another metastable Form V was obtained by spray-drying (from MeOH solution at 80 °C) that was very unstable and converted to Form III within 6 h. Spray drying, being a high surface area deposition technique, generally gives amorphous and metastable crystal forms. Thus, both Form IV and Form V converted to Form III (enantiotropic relationship). Form III is in turn enantiotropic with Form I (Figure 1). Form I is stable at

Figure 2. Polarized light microscope images of the crystallized material from solution crystallization. Form I and Form II has plate and prismatic morphology, as confirmed independently by their unit cells.

light microscope and analyzed by SEM (discussed latter). Crystallographic data and hydrogen bond values are listed in Tables 1 and 2. DADDS FORM I. Form I crystallized in space group P21/c with N−H···OC/S as the dominant hydrogen bond motif, extending via auxiliary C−H···OC/S interactions (Figure 3aI). The secondary amide N−H on both sides of the sulfone make two N−H···O hydrogen bonds (N1−H1A···O2S1: N···O, 2.906(3) Å, III > IV > V > Amorphous (least stable) and the thermodynamic stability order is Form II > I > III > IV > V > Amorphous (highest free energy). The stability order of Acedapsone polymorphs is consistent with the Ostwald’s rule of stages.26 Energy vs Temperature Diagram. A semiquantitative free energy vs temperature (G vs T) diagram was drawn based on the heat of transformation and polymorphic relationships established in our laboratory (Figure 12). Accurate melting enthalpy (ΔH) could be obtained for Forms I and II only because they show melting endotherm without additional phase transformations. The other polymorphs exhibit solid−solid phase transformations before melting. Forms I and II are monotropic according to heat of transformation rule by Burger K



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Table 5. Composition of DADDS Polymorphs under Different Preparative Conditions S. No.

Solvent for acetylation reaction

1 2 3 4 5 6 7 8 9

MeOH Acetone THF Acetonitrile EtOAc Iso-butyl methyl ketone Dichloromethane Chloroform Nitromethane

Result at 30−35 °C 5 h reaction time Form Form Form Form Form Form Form Form Form

II II I II I I I I II

Form Form Form Form Form Form Form Form Form

I+II (5 h) Form I (10 h) I (5 h) I (5 h) II (5 h) Form I (10 h) I (5 h) I (5 h) I (5 h) I (5 h) II, Form I (10 h)

Solvent Dielectric (ε)

Solvent bp (°C)

32.7 20.7 7.98 37.5 6.02 13.1 8.93 4.81 35.82

64 56 65 81 77 117 40 61 101

powder X-ray lines in PXRD did not match with either Form I or II obtained from solution crystallization. After 24−48 h the amorphous material transformed to a new metastable Form IV and then it slowly moved to another Form III at ambient conditions. Form IV has a very short lifetime of 2 days only, after which it converted to III. Under accelerated humidity conditions of 40 °C and 75% RH, the amorphous phase transformed to Form III after 24 h (Supporting Information Figure S6a and Table S2). spray-drying of DADDS dissolved in acetone again resulted in Form III occasionally. The amorphous phase finally converted to stable Form III via metastable form IV, following Ostwald’s law of stages. See Table S2, Supporting Information, for details on phase transformations. Preparation of the Metastable Form V. Form V was prepared by spray-drying after dissolving DADDS in MeOH and characterized by PXRD and DSC. It is an unstable phase and transformed rapidly to the metastable Form III within 6 h (PXRD and DSC). The basic idea of spray-drying is fast evaporation of the solvent under reduced pressure, a method that often affords amorphous and small particles size products. HSM of Amorphous Phase. Visualization of the amorphous material on Wagner-Munz Polytherm A hot stage (Supporting Information Figure S5) indicated a darkening of crystals at about 120 °C (loss of crystallinity) and melting of crystal at 280−290 °C (phase change). These observations are consistent with the sketchy description in the original report on acedapsone polymorphs.18a Further correlation of the polymorphs reported in this paper with the original observation is difficult due to the lack of spectral and diffraction data on Models I and II. Spray Dryer. Model LU-222 advanced Spray Dryer (Lab Ultima, Mumbai, India) was used to obtain a metastable phase of DADDS. The experimental conditions and parameters used to deposit the fine powder phase from MeOH and acetone solvents are listed in Table S6 (Supporting Information). Single Crystal X-ray Diffraction. Single crystal X-ray diffraction was carried at 298 K on a Bruker SMART APEX-1 CCD area detector system equipped with a graphite monochromator and a Mo Kα finefocus sealed tube (λ = 0.71073 Å) operated at 1500 W power (40 kV, 30 mA). The detector was placed at a distance of 6.003 cm from the crystal. A total of 2400 frames were collected with a scan width of 0.3° in the ω mode and an exposure time of 12 s/frame. The frames were integrated with the Bruker SAINT34a software using a narrow-frame integration algorithm. Analysis of the data showed negligible decay during data collection. Data was corrected for absorption effects using the multiscan method (SADABS). The structure was solved and refined using the Bruker SHELX-TL Software.34b A check of the final crystallographic information file (.cif) using PLATON34c did not show any missed symmetry. X-Seed34d and Mecury 3.1 were used to prepare the figures and packing diagrams. Crystallographic parameters of both crystal structures are summarized in Table 1. Hydrogen bond distances (Table 2) are neutron-normalized to fix the D−H distance to its accurate neutron value in the X-ray crystal structure. CCDC Nos. 1012181−1012182). Powder X-ray Diffraction. All new solid phases were analyzed by powder X-ray diffraction on a Bruker AXS D8 diffractometer (BrukerAXS, Karlsruhe, Germany). Experimental conditions: Cu Kα radiation (λ = 1.54056 Å), 40 kV, 30 mA, scanning interval 5−50° 2θ at a scan

solvent conditions were optimized for the preparation of a particular Acedapsone polymorph.

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Result at 130 °C 5 h/10 h reaction

EXPERIMENTAL SECTION

Preparation of Acedapsone (DADDS). Acedapsone is the diacetyl derivative of Dapsone. DADDS was prepared by the procedure of Elslager et al.12a Heating dapsone and acetic anhydride in 1:2 ratio at 60 °C (200 mg, 0.8 mmol) in the presence of AcOH (equal volume ratio, 0.45 mL) with acetic anhydride (164 mg, 152 μL, 1.7 mmol) for 5 h gave a white precipitate. Washing the solid with distilled water and drying at 70 °C for 30 min gave pure DADDS (mp 290−292 °C) in 95% yield, whose purity was checked by IR, NMR (Supporting Information Figure S3, S4), and finally confirmed by single crystal X-ray diffraction. The unprocessed material corresponds to what is identified in this report as Form II, which was used for crystallization screen experiments and novel polymorph search. Preparation of DADDS Forms I, II. Synthetic Acedapsone from the above reaction in MeOH (Form I/II by PXRD) was crystallized from a hot saturated solution in different solvents (Table 4). Both Forms I and II were obtained concomitantly/individually, which were separated by their morphology and a suitable single crystal was selected for X-ray diffraction. DADDS Form I was crystallized from EtOH/MeOH solvent exclusively, whereas other solvents gave concomitantly with Form II. DADDS Form II was crystallized from DMSO by slow evaporation over 4 weeks. Form I was crystallized from a super cool/instant cool (in 2−4 min) of the hot melt (∼300 °C). Form I was also prepared under high pressure/temperature conditions in a sealed tube using acetone as the solvent at 80 °C for 5 h, and then fast removal of solvent in a rotavap under aspirator vacuum. The difference in conditions for the nucleation of Forms I and II suggests very different solubility and supersaturation behavior of the two polymorphs (Table 4). Solvent Screen for the Synthesis of Acedapsone. The above results suggested that it should be possible to directly crystallize Form I or II from the reaction mixture and/or by carrying out the reaction in different solvent/temperature/time. The acetylation of DDS to DADDS was carried out in different organic solvents at room temperature (30−35 °C) and high temperature (130 °C) for varying lengths of time (5−10 h). The product distribution of polymorphs is presented in Table 5 and Supporting Information Table S5. The stoichiometry and solvent ratios were kept fixed as in the above procedure. Preparation of the Metastable Forms (III, IV) and Amorphous Phase. The rate of cooling of the melt phase was found to be a major parameter in Acedapsone. The first step was to prepare the amorphous form and then phase transitions to metastable polymorphs from this amorphous phase were studied. Acedapsone was melted by heating to ∼300 °C and cooling slowly to room temperature produced an amorphous phase (as suggested by PXRD with no sharp lines and a halo peak), whereas fast cooling afforded Form I (kinetic). Melting of Acedapsone followed by quench cooling experiments (fast cool) also afforded Form I. PXRD patterns of the amorphous phase were monitored every 24 h at different temperatures. There was a slow change in PXRD patterns under different conditions suggesting phase transitions. The new L



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temperature range was 30−330 °C at 5−40 °C/min. Samples were purged with a stream of dry N2 gas flowing at 80 mL/min. Solid-State NMR Spectroscopy. Solid-state 13C NMR spectra were obtained on a Bruker Ultrashield 400 spectrometer (Bruker BioSpin, Karlsruhe, Germany) utilizing a 13C resonant frequency of 100 MHz (magnetic field strength of 9.39 T). Approximately 100 mg of fine crystalline sample was tightly packed into a zirconia rotor with the help of Teflon stick up to the cap Kel-F mark. A cross-polarization, magic angle spinning (CP-MAS) pulse sequence was used for spectral acquisition. Each sample was spun at a frequency of 5.0 ± 0.01 kHz and the magic angle setting was calibrated by the KBr method. Each data set was subjected to a 5.0 Hz line broadening factor and subsequently Fourier transformed and phase corrected to produce a frequency domain spectrum. The chemical shifts were referenced to TMS using Glycine (δglycine = 43.3 ppm) as an external secondary standard. Scanning Electron Microscope (SEM). The shape, size, and morphology of the DADDS Forms I and II crystals were examined on a Philips XL30 ESEM scanning electron microscope (SEM) using a beam voltage of 20 kV. Form I and Form II were dissolved in EtOH at a very dilute concentration and further crystallized on to a 1 mm × 1 mm glass slide. The slide was placed on a carbon-coated copper grid. Prior to SEM imaging, an ultrathin layer of gold was coated using Quorum Fine coat Ion Sputter Q150R ES (operating at 10 mA for 3 min), in order to enhance the conductivity of the sample.

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ASSOCIATED CONTENT

S Supporting Information *

IR, Raman, and NMR spectra and crystallization conditions and crystallographic .cif files. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS G.B. and S.M. thank the UGC for fellowship. We thank DSTSERB Scheme on APIs (SR/S1/OC-37/2011) and JC Bose Fellowship (SR/S2/JCB-06/2009) for funding and University Grants Commission (PURSE) for providing instrumentation and infrastructure facilities.

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REFERENCES

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Figure 12. Semiquantitative G−T diagram of DADDS polymorphs. (a) Developed on the basis of polymorphic transformations as a function of temperature only, i.e., DSC and VT-PXRD. Under these conditions, Form II was not observed and Form I is the stable polymorph (referred to as the kinetically stable phase). (b) Under the conditions of stability chamber and solvent slurry, Form II is the stable phase and Form I transforms to II (referred to as the thermodynamically stable phase). rate of 1°/min, time per step 0.5 s. The experimental PXRD patterns and the calculated X-ray lines from the single crystal structure were compared to confirm the purity of the bulk phase (Forms I and II) using Powder Cell.35 Thermal Analysis. DSC experiments were performed on a Mettler Toledo DSC 822e module. Samples were placed in vented aluminum sample pans for DSC. A typical sample size is 2−5 mg for DSC. The M



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