1

Introduction

Crystal engineers are manipulating properties of the crys-talline materials through alterations in crystal form, habit or design of new crystal phases such as cocrystal. In last decade, many cocrystals have been designed to improve properties of active pharmaceutical ingredients (APIs) such as solubility, chemical stability, and compressional properties using different cocrystallization techniques.[1–10] Similarly, there are several reports showing significant differences in the properties of the material in the same crystal form obtained by different processing conditions or techniques. For example, phenytoin crystals when obtained from same solvent but at different crystallization conditions, behaved differently during compaction.[11]

Caffeine is one of the most extensively studied API for cocrystallization. Caffeine exhibits instability to humidity and poor compaction behavior. Cocrystals of caffeine were obtained in order to improve stabil-ity and compaction.[4,12–14] Dicarboxylic acid cocrystals of caffeine presented improved stability to humidity as compared to caffeine.[4] Out of different caffeine/dicar-boxylic acid cocrystals obtained, caffeine/oxalic acid 2:1 cocrystal exhibited maximum stability at higher relative humidity (7 weeks stability at 98% RH). Compaction properties of caffeine were also improved by formation of caffeine/methyl gallate 1:1 cocrystal.[13] Good plasticity and tabletability of this cocrystal was observed over caf-feine. However, no report is available indicating improve-ment in both stability and compaction of caffeine due to

RESEARCH ARTICLE

Effect of cocrystallization techniques on compressional properties of caffeine/oxalic acid 2:1 cocrystal

Suyog Aher1,2,3, Ravindra Dhumal2, Kakasaheb Mahadik1, Jarkko Ketolainen3, and Anant Paradkar2

1Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Pune, India, 2Centre for Pharmaceutical Engineering Science, University of Bradford, Bradford, UK, and 3School of Pharmacy, Pharm. Tech., University of Eastern Finland, Kuopio Campus, Kuopio, Finland

AbstractContext: Caffeine/oxalic acid 2:1 cocrystal exhibited superior stability to humidity over caffeine, but compressional behavior is not studied yet. Objective: To compare compressional properties of caffeine/oxalic acid 2:1 cocrystal obtained by different cocrystallization techniques. Materials and methods: Cocrystal was obtained by solvent precipitation and ultrasound assisted solution cocrystallization (USSC) and characterized by X-ray powder diffraction and scanning electron microscopy. Compaction study was carried out at different compaction forces. Compact crushing strength, thickness and elastic recovery were determined. Results and discussion: Compaction was in order, caffeine > solvent precipitation cocrystal > USSC cocrystal. Caffeine exhibited sticking and lamination, where solvent precipitation compacts showed advantage. Caffeine and solvent precipitation compacts showed sudden drop in compactability, higher elastic recovery with severe lamination at 20,000 N. This was due to overcompaction. Crystal habit of two cocrystal products was same, but USSC cocrystals were difficult to compact. Uniform needle shaped USSC cocrystals must be difficult to orient in different direction and fracture during compression. Elastic recovery of USSC cocrystals was also more compared to other powders indicating less fracture and poor bonding between particles resulting in poor compaction. Conclusion: Cocrystal formation did not improve compressional property of caffeine. Cocrystals exposed to different crystallization environments in two techniques may have resulted in generation of different surface properties presenting different compressional properties.

Keywords: Caffeine, compaction, cocrystal, ultrasound assisted solution cocrystallization, elastic recovery, mechanical property

Address for Correspondence: Professor Anant Paradkar, Centre for Pharmaceutical Engineering Science, University of Bradford, Bradford, West Yorkshire, BD7 1DP, UK. Tel: +44 1274 233 900. E-mail: a.paradkar1@bradford.ac.uk

(Received 29 June 2011; revised 07 August 2011; accepted 19 August 2011)

Pharmaceutical Development and Technology, 2011, 1–6, Early Online© 2011 Informa Healthcare USA, Inc.ISSN 1083-7450 print/ISSN 1097-9867 onlineDOI: 10.3109/10837450.2011.618950

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cocrystal formation. Caffeine/oxalic acid 2:1 cocrystal has presented excellent stability to humidity compared to caffeine. If this pair also demonstrates improved com-paction properties, it will provide an optimized cocrystal minimizing limitations of caffeine. The focus of the pres-ent study is comparative evaluation of compaction prop-erties of the caffeine/oxalic 2:1 cocrystal obtained using different crystallization techniques.

Caffeine/oxalic acid 2:1 cocrystal was obtained by solvent precipitation[4] and ultrasound assisted solution cocrystallization (USSC) techniques previously found to be advantageous over solvent cooling cocrystallization in obtaining pure cocrystal from a solution of a non-congruently soluble cocrystal pair with huge solubility difference.[9] Caffeine-oxalic acid also represents a non-congruently soluble cocrystal pair (approximate solubil-ity of caffeine and oxalic acid in methanol is 0.000064 mM and 0.05 mM at 25°C, respectively) and therefore can be processed by USSC to obtain cocrystal from single solvent system. Compaction behavior of caffeine/oxalic acid 2:1 cocrystal has been studied to observe any improvement in compaction property of caffeine due to cocrystal for-mation. In addition, cocrystal products of two cocrys-tallization techniques were compared for compaction properties so as to study the probable effect of cocrystal-lization techniques on product characteristics.

Materials and methods

MaterialsAnhydrous β-caffeine (≥99% pure) and oxalic acid (≥99% pure) were purchased from Sigma–Aldrich, Dorset, England. Phase purity of both compounds was verified by X-ray powder diffraction (PXRD). High-performance liquid chromatography (HPLC) grade methanol was pur-chased from Fisher Scientific, Loughborough, England and used as received without any purification.

MethodsCaffeine/oxalic acid 2:1 cocrystal preparation

Solvent precipitation: Caffeine/oxalic acid 2:1 cocrystal was obtained as described by Trask et al.[4] Anhydrous β-caffeine (4.85 g; 25.0 mM) and oxalic acid (1.12 g; 0.5 eq of caffeine) were dissolved in 90 mL of 7:2 (v:v) chlo-roform/methanol solvent system by heating to reflux. The solution was concentrated using vacuum and pre-cipitated solids were separated by filtration, and dried overnight at 30°C. Dried solids were kept in desiccators until further study.USSC: Cocrystallization from solution was carried out using the equipment consisted of a probe and high inten-sity ultrasonic processor/sonifier (Sonics and Materials Inc., Vibra Cell, Model VCX 500, Connecticut, USA) with temperature controller microprocessor. A high intensity solid probe with tip diameter of 13 mm, was immersed in the processing liquid. This device was operated at a fixed wavelength of 20 kHz and capable of inducing a maxi-mum power output of 500 W.

Caffeine and oxalic acid were added in equimolar ratio (0.00773 M) in 75 mL methanol and dissolved by heating the system at 55–60°C. The clear solution was subjected to several ultrasound pulses in a jacketed glass sonore-actor vessel using a high intensity ultrasound probe (an ultrasound pulse of 10 s with relaxation time of 2 s was employed). Cool water (15 ± 2°C) was circulated through glass sonoreactor jacket during sonication using circu-lating water bath. Typically, 6–9 pluses were employed and sonication was stopped when solution became tur-bid. Solids were separated by filtration, rinsed with cold methanol and dried overnight at 30°C. Dried solids were kept in desiccators until further study.

Physical characterizationPXRD: PXRD patterns of different samples were recorded using a Bruker D8 diffractometer (wavelength of X-rays 0.154 nm Cu source, voltage 40 kV, and filament emission 40 mA). Samples were placed into a sample specimen holder and scanned from 2 to 30° 2θ using step size of 0.02° 2θ, step time of 2 s and sample rotation of 30 rpm. The receiving slit was 1° and the scatter slit was 0.2°. The data were analyzed using DIFFRACplus EVA (Version 11.0) software.Scanning electron microscopy (SEM): Crystal habit and particle size distribution of different products was visu-alized using SEM. The surface topography was analyzed with Quanta 400 scanning electron microscope (FEI, Oregon, USA) operated at an acceleration voltage of 25 kV. Extensible threat management (ETM) microscope con-trol software version 2.3 was used for imaging. Samples were mounted on a stainless steel stub using adhesive carbon tabs.

Compaction study: Compaction was carried out using Caleva Compaction Study Press (Caleva Process Solutions Ltd, Dorset, England) coupled with Compaction Study Press Powder v.10.1 software. Flat round punch tool-ing of 10 mm was used which was lubricated each time with magnesium stearate prior to compaction. Powder products of solvent precipitation and USSC (particle size < 100 µm) were used for compaction. Die cavity was filled with either of the powder (caffeine/solvent precipita-tion cocrystal/USSC cocrystal) weighing 200 ± 2 mg and five compacts were prepared each at 2000, 5000, 10,000, and 20,000 N force. An attack rate of 100 mm/s and dual time 0.1 was employed during compaction. Thickness and crushing strength of each compact was measured immediately after compact preparation using thickness gauge instrument (digital type) (Mitutoyo Corporation, Kanagawa, Japan) and Schleeuniger− 4 M hardness tes-ter (Copley Instruments, Nottingham, UK), respectively. Compacts were also analyzed visually for surface smooth-ness. Elastic recovery for each compact was calculated using the following equation,

% ER = 100 ( )0

0

h h

h

− (1)

where, h is the height of compact after compaction stress reaches zero at the end of the decompression phase and

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h0 is the height of compact under maximum compaction

pressure.

Results and discussion

The product obtained by solvent precipitation was in the form of needle shaped crystals, which can be easily visualized by naked eyes. However, the product observed after cessation of sonication in USSC was in the form of fine suspended particles. Filtration and drying of these particles resulted in loose agglomerated product.

X-ray powder diffractionAn overlay of PXRD patterns for caffeine, product obtained by solvent precipitation and USSC are shown in Figure 1. PXRD pattern of solvent precipitation cocrys-tal was used to confirm cocrystal formation in USSC. Cocrystal characteristic peaks were observed at 8.2, 12.0, 12.7, 16.4, 17.8 and 18.8° 2θ. During preliminary study using USSC, it was observed that when caffeine and oxalic acid were taken in 2:1 molar ratio in methanol (same as their stoichiometric ratio in cocrystal), the PXRD pat-tern was not identical with that of product obtained by solvent cooling indicating presence of caffeine (data not shown). With further increase in oxalic acid amount in methanol, caffeine: oxalic acid 1:1 molar ratio in metha-nol, presented identical diffractogram as that of solvent precipitation cocrystal. Therefore, caffeine: oxalic acid 1:1 molar ratio in methanol was considered as opti-mized one to obtain cocrystal by USSC. Caffeine: oxalic acid stochiometry in cocrystal is 2:1, but 1:1 molar ratio was used in methanol. This indicate that while obtain-ing cocrystal from non-congruently soluble cocrystal pair in USSC, high soluble cocrystal component (oxalic acid in present case) may be required in excess ratio in

processing solution, compared to cocrystal stoichiomet-ric ratio. Results are in accordance with previous report of USSC for non-congruently soluble cocrystal pair.[9] The exact role of sonication in solution crystallization or USSC is poorly understood. However, reduction in induction time and metastable zone width was thought to be responsible for crystallization phenomenon.[15–17] This collectively must have resulted in altered supersatu-ration levels of caffeine and oxalic acid during sonication in USSC presenting caffeine/oxalic acid 2:1 cocrystal. USSC presented advantage over solvent precipitation with respect to processing time and use of single solvent system.

Scanning electron microscopySEM images of cocrystals obtained by solvent precipi-tation and USSC are shown in Figure 2. In both cases, needle shaped crystal habit was observed. Solvent pre-cipitation cocrystals were of wide size range staring from few micrometers to few millimeters (20 µm–2 mm). This observed variation was due to slow removal of solvent by vacuum, which usually gives rise to well-grown crystals with smooth surface.[18] However, product of USSC pre-sented crystals in much narrow size range (20–150 µm) compared to solvent precipitation. USSC cocrystals were in the form of loose floppy agglomerates of needle shaped crystals (Figure 2c). USSC favored generation of primary nuclei over crystal growth which presented crystals in narrow size range. On the contrary, solvent precipitation provided uncontrolled nucleation and crystal growth environment leading to wide particle size distribution. USSC presented advantage to generate small size par-ticles in narrow range using one step process, whereas solvent precipitation crystals need to be milled further to get uniform small size particles.

Figure 1. Overlay of PXRD patterns of caffeine, and cocrystal obtained by solvent precipitation and USSC.

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During application of ultrasound to solution in USSC, nucleation from particle free solution is affected by the presence of cavitation energy of ultrasonic waves. This cavi-tation phenomenon can achieve supersaturation easily or induce primary nucleation at lower supersaturation levels by reducing the induction period and metastable zone width.[15–17,19] Because of this, more number of primary nuclei must have formed and ultimately presenting more fine and uniform particles compared to solvent precipitation.

CompactionResults of compaction study are presented in Table 1 and elastic recovery of different compacts is shown in Figure 3. Compaction behavior of different compacts was in the order, caffeine > solvent cooling cocrystal > USSC cocrystal. During compaction of caffeine, sticking was observed at all compaction forces and therefore compact surfaces were rough. Intact compacts were observed at lower compaction force and lamination was observed

Figure 2. SEM images of cocrystals obtained by solvent precipitation (a) and USSC (b and c).

Figure 3. Elastic recovery of caffeine and cocrystal obtained by solvent precipitation and USSC as a function of compaction force.

Table 1. Results of compaction study.

Compaction force (N)

Caffeine Solvent precipitation cocrystal USSC cocrystalThickness (mm) Crushing strength (Kp) Thickness (mm) Crushing strength (Kp) Thickness (mm) Crushing strength (Kp)

1000 1.95 ± 0.06 1.8 ± 0.4 1.92 ± 0.05 2.1 ± 0.3 2.17 ± 0.08 0.7 ± 0.55000 1.92 ± 0.04 4.8 ± 0.6 1.86 ± 0.04 2.7 ± 0.5 2.11 ± 0.05 -

10,000 1.91 ± 0.07 3.7 ± 1.8 1.82 ± 0.06 3.1 ± 0.5 2.08 ± 0.03 -

20,000* 1.90 ± 0.08 1.1 ± 0.7 1.80 ± 0.08 1.2 ± 0.4 2.05 ± 0.08 -

Observations Sticking to punches and lamination, tablet surface rough

Tablet surface smooth, lamination at 20,000 N

Weak compacts, lamination at all forces.

*Results reported for three compacts.

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with increase in compaction force. The observed com-paction behavior of caffeine was in agreement with previ-ous caffeine compaction reports.[13] Crushing strength of caffeine compacts was increased from 1000 to 5000 N, but decreased with further increase in compaction force. Similarly, elastic recovery was also increased with increase in compaction force and sudden increase was observed at 20,000 N. Poor compaction observed at 20,000 N sug-gests unfavorable effect of elastic recovery on compact strength i.e. reduced bonding strength between particles due to elevated pressure.[13] In addition, sever lamination was observed at 20,000 N, indicating poor compaction. This must be due to overcompaction.

Caffeine/oxalic acid 2:1 cocrystal formation did not improve compaction behavior of caffeine. Thickness of solvent precipitation compacts was slightly less than that of caffeine compacts at same compaction force (p > 0.05, t-test), but no improvement in crushing strength was observed. Elastic recovery in solvent precipitation cocrys-tal compacts was also less compared to caffeine, which may be due more fracture of particles in former resulting in better rearrangement of particles during compression. However, the bonding strength of solvent precipitation cocrystals in compacts was not enough to present better compact than caffeine. Compacts of solvent precipita-tion cocrystals did not show sticking and compact sur-faces were smooth. Crushing strength of these compacts increased with increase in compaction force from 1000 N to 10,000 N. Similar to caffeine, these compacts also exhibited sever lamination at 20,000 N. Crushing strength at this point decreased significantly and elastic recovery increased. This poor compaction behavior at higher com-paction force must be due to overcompaction.

USSC cocrystals exhibited very poor compaction behavior compared to both caffeine and solvent precipi-tation cocrystal compacts. Though few intact compacts were obtained using USSC cocrystals, those were very weak as observed during crushing strength determi-nation. A typical behavior of USSC compacts during crushing strength determination is shown in Figure 4. With increase in force along the direction of USSC com-pact thickness during crushing strength determination, compact did not shatter in pieces all of a sudden. Rather,

compact deformed slowly till driven jaw traveled its maximum displacement and no crushing strength mea-surement was obtained. This indicates very week bond-ing between particles of USSC compact. This was also evident from significantly higher elastic recovery values of USSC cocrystal compacts compared to both caffeine and solvent precipitation cocrystal compacts.

Particle shape is known to affect compact strength for materials which fragment to a limited degree dur-ing compaction.[20–22] Better compaction was observed in case of particles of more irregular size and shape. In present case, uniform sized needle shaped USSC cocrys-tal must be difficult to orient in different direction and fracture during compaction resulting in poor compac-tion. In contrast, solvent precipitation cocrystals were of different sizes and shapes. Fines from this product must have filled cavities between comparatively larger particles. This presented better compaction behavior of solvent precipitation product over USSC.

In addition, cocrystal obtained by two different tech-niques exhibited similar habits, but elastic properties of these crystals were different which has presented differ-ent compaction properties and further need to be stud-ied in detail. Two cocrystallization techniques may have different effect of cocrystal surface properties, which resulted in immensely different compaction behavior. Ultrasound application in crystallization has shown to alter the morphology and crystal habit[23,24] and also significantly different properties compared to simple solution crystallization.[25–27] Therefore, surface proper-ties of these cocrystal products need to be studied so as to understand the difference in compaction behavior. It has been reported that crystals exhibiting flat layers that are hydrogen-bonded correspond to better plasticity and tabletability.[28] Though caffeine/oxalic acid 2:1 cocrystal contains hydrogen-bonded structure, flat layers may not be available for fracture resulting in poor compaction.

Conclusion

Caffeine/oxalic acid 2:1 cocrystal has shown better sta-bility to humidity, but failed to improve poor compac-tion behavior of caffeine. Though, cocrystal obtained by

Figure 4. Behavior of USSC cocrystal compacts during crushing strength determination.

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different cocrystallization techniques showed similar crys-tal habit, mechanical properties were dramatically differ-ent. Cocrystals exposed to different processing conditions in different techniques are expected to possess different surface properties and mechanical properties, which need to be studied in detail at nanoscale. Efforts should also be given to design a new cocrystal of caffeine using crystal engineering strategies, which can improve stability to humidity as well as compaction property of caffeine.

Acknowledgments

Suyog Aher is thankful to Centre for Pharmaceutical Engineering Science, University of Bradford, Bradford, UK for providing research facilities.

Declaration of interest

We are very thankful to Centre for International Mobility (CIMO), Helsinki, Finland for providing the CIMO-India Fellowship (23.4.2010/TM-10-6968/Cimo India Fellowship). Suyog Aher is grateful to All India Council for Technical Education (AICTE, New Delhi, India) for providing financial support in the form of National Doctoral Fellowship (AICTE-NDF).

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