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Cocrystal dissociation under controlled humidity: A case study of caffeine-glutaric acid cocrystal polymorphs Ranjit Thakuria, Mihails Arhangelskis, Mark D. Eddleston, Ernest H. H. Chow, Kashyap Kumar Sarmah, Barry J. Aldous, Joseph F. Krzyzaniak, and William Jones Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00422 • Publication Date (Web): 28 Feb 2019 Downloaded from http://pubs.acs.org on February 28, 2019

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Organic Process Research & Development

Cocrystal dissociation under controlled humidity: A case study of caffeine-glutaric acid cocrystal polymorphs Ranjit Thakuria,1,2,* Mihails Arhangelskis,3 Mark D. Eddleston,2 Ernest H. H. Chow,2 Kashyap Kumar Sarmah,1 Barry J. Aldous,4 Joseph F. Krzyzaniak,5 and William Jones2,* 1Department

of Chemistry, Gauhati University, Guwahati 781014, Assam, India

2Department

of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW,

United Kingdom 3Department

of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal H3A

0B8, Canada 4Antiva

Biosciences, Inc. 6000 Shoreline Court, Suite 203, South San Francisco, CA 94080,

USA 5The

Pfizer Institute for Pharmaceutical Material Science, Pfizer, Groton, CT, (USA)

ACS Paragon Plus Environment

Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Abstract: Caffeine-glutaric acid cocrystal polymorphs, Form I and Form II, are presented as a model system to study cocrystal dissociation under controlled humidity. Based on relative humidity (RH) data it was observed that Form I transforms to Form II at high RH with the rate of polymorphic phase transformation increasing with increase in RH with the relative stability of the cocrystal following a similar trend to that of coformer deliquescence point for other caffeine dicarboxylic acid cocrystals. In addition, reduction in particle size, change in crystal morphology with greater number of crystal faces exposed to surrounding atmosphere and internal arrangement of molecules in the crystal structure are shown to influence cocrystal instability and favor dissociation under increased humidity. Keywords: Cocrystal, Polymorph, Stability, Particle size, Crystal defects, Deliquescence point. Introduction The stability of a drug under conditions of high humidity is an important consideration in the development of new solid pharmaceutical forms. As humidity varies depending on the geographical altitudes and climatic conditions, a detailed investigation of drug stability under different humidity conditions is essential for drug manufacturing, processing, storage, transportation, pharmaceutical activity as well as patentability. Many pharmaceutical materials undergo dissociation/ decomposition at high humidity and other stress conditions (for example high pressure, mechanical stress etc).1 As a consequence, therefore, solid-state modification through the preparation of polymorphs,2-4 or multicomponent solids (e.g. solvates,5-7 salts8-10 and cocrystals11-16) may be required during the development of an active pharmaceutical ingredient (API). Polymorphism in single component17 and multicomponent systems18 is quite common. An additional complication for multicomponent solids is the possibility of producing diverse solid-state forms such as variable stoichiometry cocrystals,1923

as well as crystallization of individual components.24-27 Before considering a

pharmaceutical (potentially) polymorphic cocrystal for drug formulation, the following questions, therefore, need to be addressed: 1. Can these materials be prepared on a large scale? 2. Are they stable towards hydration? 3. Are they stable under mechanical stress such as grinding, compression and compaction? 4. Does particle size reduction influence stability?



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Therefore, the selection of a polymorphic cocrystal system as a model is particularly relevant to investigate these issues. Caffeine, a methylxanthine alkaloid, is a central nervous system stimulant and one of the most widely consumed psychoactive drugs. It is also a food additive found as a major ingredient of coffee beans and tea. Two anhydrous crystal forms of caffeine (polymorphs α and β) have been reported.28 In the presence of atmospheric moisture anhydrous caffeine readily converts to a non-stoichiometric hydrate.29,30 Trask et. al.31 prepared cocrystals of caffeine with a series of dicarboxylic acids viz. oxalic, malonic, maleic, glutaric acid and investigated their relative hydration stability under various controlled humidity conditions. During the preparation of the cocrystals, two polymorphic cocrystals with glutaric acid were identified

under

conditions

of

mechanochemical

synthesis

as

well

as

solution

crystallization.32 In a recent report Mukherjee et. al.33 isolated the two polymorphs using imidazolium-based ionic liquid assisted grinding (IL-AG). In addition, thermal analysis and the stability during milling of these two polymorphs (Form I and Form II) has been extensively studied by Vangala and coworkers.34,35 Cassidy et. al.36 reported the surface response of caffeine-oxalic and caffeine-malonic acid cocrystals under controlled humidity conditions using atomic force microscopy (AFM) and scanning electron microscopy (SEM). Thakuria et. al.37 extended this study by performing in-situ AFM measurements under controlled humidity as a characterization tool, proposed a mechanism for the polymorphic phase transition as well as compared various surface techniques to discriminate the two polymorphs.38 Eddleston et. al.39,40 rationalized cocrystal dissociation of several model API cocrystals using ternary phase diagrams. Extending dissociation study of multicomponent solids, Thakuria and coworkers41 carried out a case study on hydration stability of pharmaceutical salts under controlled humidity using powder X-ray diffraction (PXRD) as a characterization tool. Herein, we present a further study of the caffeine-glutaric acid dimorphic cocrystal system as a model to investigate the mechanism of cocrystal dissociation under high humidity and the influence of particle size, crystal morphology, crystal packing as well as hydration stability of coformer on overall stability of corresponding cocrystals. Experimental section All the chemicals were purchased from Sigma–Aldrich and used as received without further purification. Caffeine-glutaric acid cocrystal polymorphs were prepared by grinding stoichiometric amounts of coformers with a total sample weight of approximately 98 mg in a


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Retsch MM200 ball mill for 30 min at a frequency 30Hz using metal jars of 50 ml volume with two 7 mm diameter stainless steel grinding balls. Cocrystal Form I (Monoclinic, P21/c; T = 180 K; a = 13.0129 Å, b = 6.6017 Å, c = 17.1427 Å, β = 97.836°) was obtained using liquid-assisted grinding (LAG), adding 20 μl of hexane to the grinding jar, whereas Form II (Triclinic, P1; T = 180 K; a = 8.3212 Å, b = 8.6667 Å, c = 11.3636 Å, α = 68.955°, β = 78.559°, γ = 74.236°) was prepared by adding 20 μl of chloroform. Solution crystallizations were carried out in 50 mL conical flask under conditions similar to those reported elsewhere.38 Humidity studies were performed at ambient temperature in bell jars containing saturated salt solutions (phosphorous pentoxide to give a RH of 0%, potassium oxalate to give a RH of 23%, saturated aqueous potassium carbonate solution to give a RH of 43%, saturated aqueous sodium chloride solution to give a RH of 75%, potassium chloride to give a RH of 85%, potassium sulphate to give a RH of 98%). Powder samples were removed from the jars at regular time intervals and analyzed using a Panalytical X’Pert Pro powder diffractometer with CuKα radiation at a wavelength of 1.5418 Ǻ. Data were collected between 3° and 50° 2θ at ambient temperature. Rietveld refinement42 of the crystal structures was performed using the software TOPAS Academic.43 Diffraction peak shapes were modeled using a Pseudo-Voigt function, optimal peak shape parameters were obtained by measuring the powder pattern of the reference standard material (LaB6, SRM 660a). Crystallite size effect was modelled using Lorentzian broadening. The background was represented by a Chebyshev polynomial function. The refinable parameters included background polynomial coefficients, zero shift, unit cell parameters and size broadening. The atomic coordinates were fixed at the values determined from single crystal measurements. Water vapor sorption profiles were determined at 25 °C using DVS-1 moisture sorption analyzer from Surface Measurement Systems, United Kingdom. The DVS experiments were used to study various set target humidity levels, as indicated by the “Target RH” graphs (Figure 2 & 3). About 5.88 mg of Form I was subjected to RH flux from 0% to 98% in 5 steps (0 % RH 2 mins, 43% RH 72 mins, 75% RH 51 mins, 84%RH 66 mins and 98% RH 1211 mins) and 17.47 mg of Form II in 8 steps (0% RH 80 mins, 30% RH 70 mins, 50% RH 70 mins, 60% RH 124 mins, 70% RH 100 mins, 80% RH 100 min, 90% RH 178 mins and 98% RH 178 mins). A change in target humidity was triggered once the sample weight was steady such that the rate of change in mass dropped below a default threshold.



Images of the caffeine-glutaric acid polymorphic cocrystals were obtained using Zeiss Supra 40VP scanning electron microscope (SEM) and Sigma-300, ZEISS field emission scanning electron microscope (FESEM). Results and Discussion The studied 1:1 caffeine-glutaric acid cocrystal polymorphs (Form I and Form II) were prepared using LAG as well as solution crystallization. Solution crystallization experiments resulted in the concomitant formation of the corresponding cocrystal polymorphs along with trace amounts of unreacted starting materials. LAG using nonpolar solvents such as hexane, heptane, carbon tetrachloride etc. produced Form I along with a trace of Form II as impurity in one instance (see Table 1, sample at 0 day under 23 % RH). Form II, on the other hand, was obtained with 100% purity using solvents such as acetonitrile, chloroform, cyclohexene, 1:1 chloroform ethylacetate mixture, dioxane, ethylacetate, ethanol, toluene, p-xylene, nitromethane, and water (Figure S1). Rietveld refinement42 of the PXRD data was used for quantitative analysis of cocrystal dissociation. Controlled humidity experiments RH stability and cocrystal dissociation analyses of caffeine-glutaric acid polymorphic cocrystals (Form I and Form II) were performed on powder samples prepared using LAG. The outcome of humidity-controlled cocrystal dissociation experiments is summarized in Table 1. Table 1 Phase composition of Forms I and II under various controlled RH. The proportions of Form I, Form II and caffeine hydrate are shown in red, light blue and black, respectively. (data points which were not obtained were estimated based on adjacent humidity data collected after regular intervals – see SI)


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The following observations from Table 1 can be derived: 1. Form I could not be prepared with 100 % purity using LAG and contains a small amount (~ 5 %) of Form II in one instance (sample at 0 day under 23 % RH). Form II, however, could be prepared with 100 % purity. 2. Form I converts to Form II within a day at 98 % RH, with the conversion rate of Form I to Form II increasing with increase in RH. We note that traces of Form II impurity present in Form I may act as a seed for polymorphic phase transition which further leads to cocrystal dissociation although Form II is stable up to 1 week under similar conditions. 3. Prolonged storage (2-7 weeks) of samples of Form II* (i.e. the Form II resulting from transformed Form I) and freshly prepared Form II results in cocrystal dissociation and the formation of caffeine hydrate. Needle shaped caffeine hydrate crystals growing on the surface of Form II crystals can be seen under optical microscope image as well as AFM height image (Figure 1). (Preferred orientation was observed during Rietveld refinement of PXRD data collected after 2 weeks under 98% RH)



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4. Under conditions of 98 % RH, the dissociation rate of Form II* is relatively low (4 % of caffeine hydrate formed after 7 weeks, see Table 1) when compared to that of freshly prepared Form II powder (20 % of caffeine hydrate formed after 7 weeks, see Table 1). This may be attributed to the morphological variation of two starting polymorphs and different reactivity of the crystal faces exposed to humidity. 5. Dissociation of the cocrystals is also influenced by particle size and likely crystal defects induced during grinding. Millimeter sized crystals (Figure S3) of Form I show a slower conversion to Form II compared to micrometer sized (0.2–3 μm) powder materials (Figure S4 and S5) under similar humidity conditions (See Table S1).

(a)

(b)

Figure 1 Needle shaped crystals of caffeine hydrate grown on surface of caffeine-glutaric acid Form II under 98% RH on prolonged storage shown using (a) optical microscope image and (b) AFM height image (white protrusion). Dynamic vapor sorption (DVS) Dynamic vapor sorption isotherms were recorded in order to support the RH study. The DVS plot of Form I (Figure 2) shows that the sample takes up less than 1% water w/w at 84% RH. At 98% RH, there is a much larger water uptake (~ 16%) which may be due to adsorption of water by the cocrystal or deliquescence of glutaric acid. On prolonged storage (~ 13hr), however, a loss of water (~ 10%) occurs. The weight loss was shown to coincide with dissociation of Form I, as confirmed by PXRD analysis (Figure S2). The Form II cocrystal also showed water uptake of less than 1% at up to 90% RH. Approximately 9 % water was taken up on at 98% RH over 3 hours. This analysis was not extended over the same time range as for the Form I sample, so maximum water uptake by the sample was not determined (Figure 3). Water is taken up more quickly by the Form II sample than Form I at 98% RH.


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This could be influenced by sample mass (5.88 mg for Form I and 17.47 mg for Form II) and morphology differences.

Figure 2 DVS isotherm of caffeine-glutaric acid cocrystal Form I

Figure 3 DVS isotherm of caffeine-glutaric acid cocrystal Form II The results of the present work together with an earlier study31 on hydration stability of caffeine-dicarboxylic acid cocrystals under various controlled humidity conditions, allow



us to rank the cocrystals in the order shown in Scheme I. Comparison of cocrystal stability with the published deliquescence points of the corresponding dicarboxylic acids44 shows a good correlation with the relative hydration stability of the cocrystals following a similar trend to that of the deliquescence points of the dicarboxylic acids. Caffeine-oxalic acid cocrystal is the most stable towards dissociation, and so is the single component oxalic acid. Another important observation from Scheme 1 is, the improved stability against moisture of Form II compared to Form I possibly resulting from the lower lattice energy (Form I = – 243.7 kJ/mol; Form II = –254.1 kJ/mol) of Form II due to the presence of additional hydrogen bonds (Table S2).

Scheme 1 Relative hydration stability order of caffeine-dicarboxylic acid cocrystals compared with deliquescence point of coformer dicarboxylic acids. Relative stability against moisture would also appear to be further dependent on the morphology of the crystals.45-47 From solution crystallization experiments it is observed that Form I is lath shaped and freshly prepared Form II is block shaped with multiple crystal faces exposed to the external environment. From Table 1, transformed Form I i.e. Form II* with lath shaped morphology is more stable compared to freshly prepared Form II having block shaped morphology under identical humidity conditions. An explanation for this may be attributed to the presence of a smaller number of crystal faces exposed to the surrounding atmosphere for Form II* (with a lath shaped morphology) compared to freshly prepared Form II (with a block shaped morphology) and difference in reactivity of crystal faces towards atmospheric moisture. This statement is further supported by SEM images of freshly prepared Form II (block shaped) and Form II* (lath shaped) crystals of caffeine-glutaric acid. Rod shaped crystals of caffeine hydrate were seen protruding from the minor face (010) compared to small needles growing from dominant (001) crystal face of freshly prepared block shaped


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Form II under exposed humidity. Transformed Form I (i.e. Form II*) with lath shaped morphology shows similar needles growing from the dominant (001) crystal face (Figure S6). BFDH morphology prediction using Mercury 3.10 also shows (Figure 4) a higher number of hydrophilic groups (carboxylic acid group of glutaric acid) exposed to crystal surface in the block shaped Form II compared to the lath shaped Form I crystal. As a result, atmospheric moisture can interact with molecules exposed to the crystal surface of Form II much faster compared to Form I.

(a)

(b)

Figure 4 BFDH morphology of (a) Form I and (b) Form II of caffeine-glutaric acid cocrystal calculated using Mercury 3.10 showing molecules exposed to the crystal surface. Conclusions We have carried out an investigation of the hydration stability and cocrystal dissociation of a model polymorphic cocrystal system, caffeine-glutaric acid under different controlled humidity conditions. Effects of lattice energy, crystal morphology, particle size, crystal defects induced during grinding and relative stability of coformers on cocrystal dissociation have been investigated for this polymorphic cocrystal system. Based on the acquired evidence a mechanism involving polymorph transformation followed by deliquescence and recrystallization of caffeine hydrate can be proposed (Scheme 2).



Scheme 2 Stepwise mechanism of caffeine-glutaric acid Form I dissociation under 98% RH. The hydration stability of all the dicarboxylic acid cocrystals of caffeine follows a similar trend to that of the deliquescence point of the corresponding dicarboxylic acid, with the oxalic acid cocrystal being the most stable. The two glutaric acid cocrystal polymorphs show differences in their relative stability which reflects influence of hydrogen bonding, crystal packing, crystal morphology, defects induced during grinding and particle size on cocrystal stability under high humidity. We believe this kind of investigation will definitely help in screening pharmaceutical cocrystals for drug development and formulation in the near future. Acknowledgements R.T. is grateful to Department of Science and Technology (DST) for a SERB Young Scientists project (Project No. SB/FT/CS-101/2013) and the Pfizer Institute for Pharmaceutical Materials Science, E.H.H.C. to the Pfizer Institute for Pharmaceutical Materials Science, M.A. to EPSRC for a PhD studentship, K.K.S. to CSIR-SRF for PhD studentship and M.D.E. to the EU INTERREG IVA 2 Mers Seas Zeeën Cross-border Cooperation Programme for financial support. Notes and references Corresponding Author *E-mail: [email protected], [email protected], [email protected] Notes The authors declare no competing financial interests. Supporting Information Supporting information file contains Figure S1 PXRD patterns of caffeine-glutaric acid polymorphs synthesized using LAG, Table S1 Phase composition of Form I crystals under controlled humidity, Table S2 Hydrogen bond interactions of Form I and Form II cocrystal, Figure S2 Rietveld refinement data of polymorphs under various RH, Figure S3 Optical images of millimeter sized caffeine-glutaric acid cocrystal polymorphs prepared using solution crystallization, Figure S4 SEM images of Form I and Form II powder prepared using NG and LAG, Figure S5 PXRD of the respective powder samples used for SEM analysis to confirm their phase purity and Figure S6 SEM images of Form I and Form II crystals under exposed humidity.


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Cocrystal dissociation under controlled humidity: A case study of

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