Cryosynthesis of co-crystals of poorly water-soluble pharmaceutical

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Cryosynthesis of co-crystals of poorly water-soluble pharmaceutical compounds and their solid dispersions with polymers. “Meloxicam - succinic acid” system as a case study. Andrey Ogienko, Svetlana Myz, Anna Ogienko, Andrey Nefedov, Andrey S. Stoporev, Maxim S. Mel'gunov, Alexander S. Yunoshev, Tatiana Shakhtshneider, Vladimir V. Boldyrev, and Elena Boldyreva Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b01070 • Publication Date (Web): 01 Nov 2018 Downloaded from http://pubs.acs.org on November 4, 2018

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Crystal Growth & Design

Cryosynthesis of co-crystals of poorly water-soluble pharmaceutical compounds and their solid dispersions with polymers. “Meloxicam - succinic acid” system as a case study.

Andrey G. Ogienkoa,b*, Svetlana A. Myzb,c, Anna A. Ogienkob,d, Andrey A. Nefedovb,e, Andrey S. Stoporeva,b,f, Maxim S. Mel’gunovb,g, Alexander S. Yunoshevb,h, Tatyana P. Shakhtshneiderb,c, Vladimir V. Boldyrevb,c, and Elena V. Boldyrevab,g* a

Nikolaev Institute of Inorganic Chemistry, Siberian Branch of the Russian Academy of Sciences,

630090, Novosibirsk, Russia b

Novosibirsk State University, Department of Natural Sciences, 630090, Novosibirsk, Russia

c

Institute of Solid State Chemistry and Mechanochemistry, Siberian Branch of the Russian Academy

of Sciences, 630128, Novosibirsk, Russia d

Institute of Molecular and Cellular Biology, Siberian Branch of the Russian Academy of Sciences,

630090, Novosibirsk, Russia e

N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian

Academy of Sciences, 630090, Novosibirsk, Russia f g

Gubkin University, Department of Physical and Colloid Chemistry, 119991, Moscow, Russia Boreskov Institute of Catalysis, Siberian Branch of the Russian Academy of Sciences, 630090,

Novosibirsk, Russia h

Lavrent’ev Institute of Hydrodynamics, Siberian Branch of the Russian Academy of Sciences,

630090, Novosibirsk, Russia Synopsis This work illustrates the potential of freeze-drying for obtaining pharmaceutical сo-crystals from the components that differ drastically in their solubilities. Abstract Co-crystals of pharmaceutical compounds are widely used to improve the properties of drug formulations, such as dissolution behavior, bioavailability, or tabletability. The main methods of their synthesis include co-crystallization from solution, melt, or co-grinding. Only a few examples have been documented when co-crystals have been obtained by freeze-drying, namely in the systems where the components of a target co-crystal had similar aqueous solubilities. This work illustrates the potential of freeze-drying for obtaining pharmaceutical co-crystals when the solubilities of individual components differ drastically. Co-crystals of a model system – meloxicam and succinic acid – could be obtained both as a pure crystalline phase and forming a solid dispersion with a polymeric carrier. ACS Paragon Plus Environment

Crystal Growth & Design 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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We show that even for the pharmaceutical compounds with very low aqueous solubility co-crystals with well-soluble co-formers can be successfully produced under well-optimized conditions of cooling and subsequent freeze-drying. The rate of release of meloxicam from the fine solid dispersion of its co-crystal with succinic acid in polyethylenglycol obtained by freeze-drying was significantly higher than dissolution rates of a) pure meloxicam co-crystals with succinic acid obtained by different variants of freeze-drying (thin film freezing, TFF, and spray freeze-drying, SFD), b) powder of meloxicam co-crystal with succinic acid obtained by liquid-assisted co-grinding. The possibility to obtain co-crystals of components with very different aqueous solubilities not only by TFF or SFD techniques, but also by freezing solutions in vials at temperatures significantly higher than that of liquid nitrogen was shown. Introduction Pharmaceutical co-crystals (co-crystals of active pharmaceutical ingredients, API, with pharmacologically acceptable co-formers) are attracting much attention in relation to their improved (as compared to pure API) dissolution kinetics, membrane permeability, chemical and physical stability on storage, lower hygroscopicity, better tabletability, and other properties, which are important for bioavailability and therapeutic effect, for handling of the formulations during production, storage, and transportation, as well as for the issues related to the intellectual property.15

Co-crystals can be produced by various techniques, such as co-crystallization from solutions on slow evaporation6-8, or by using anti-solvents9. For the components that do not decompose on heating, spray-drying10, as well as crystallization from supercritical CO2 are applied11,12. Co-melting is a popular method when components can melt without decomposition.7,13 In many cases the cocrystals that cannot be formed by any other technique can be produced easily by various types of mechanical treatment, such as co-grinding14-23, extrusion24,25, ball-milling26-34, wet-milling35,36, or resonance acoustic mixing37,38. Another technique that is popular for producing fine powders of APIs and their solid dispersions is freeze-drying.39 However, only very few examples of applying this technique for the synthesis of multi-component crystalline materials have been documented.40-42 Freeze-drying is usually applied to obtain fine powders of water-soluble compounds with desired physicochemical properties, such as enhanced dissolution rates and/or bioavailability.43-44 Thin film freezing technique (TFF), when a solution is splashed over a plate preliminary cooled to the temperature of liquid nitrogen, is promising not only for the solubilization of poorly water-soluble APIs as individual compounds45, but also for obtaining crystalline forms (co-crystals, polymorphs, solid dispersions with polymers) that cannot be obtained by alternative techniques, or can be obtained with great difficulties. Earlier, the potential of the TFF method has been illustrated for a “glycine-

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water” system. In contrast to spraying the solution into a container with liquid nitrogen46, the TFF method with subsequent phase separation of the frozen solution47, proved to be efficient for obtaining a “glycine elusive phase”, in amounts, sufficient to measure a good quality PXRD pattern, that made it possible to identify it as glycine dihydrate (DGH)48, as well as to follow the processes of its formation and decomposition. For a “paracetamol-pyridine” system a new solvate could be obtained only if TFF was used, whereas classical methods (crystallization from solution on cooling or on solvent evaporation) gave exclusively monoclinic paracetamol, or a non-crystalline oily precipitate.49 At the same time, freeze-drying of solutions in organic solvents is a challenge because of several reasons that include toxicity, high degree of flammability or explosion potential, low melting temperatures of the solvents and consequently the difficulty to optimize the drying rate, in order to make the process economically feasible.50 For the compounds with low aqueous solubility one can use mixtures of organic solvents with water that form crystalline clathrate hydrates on freezing.51 Freeze-drying the clathrate-forming solution under carefully selected conditions makes it possible to eliminate the components of the mixed solvent, the solute (the API and excipients, if added) remaining as large porous particles (LPP).52 These LPPs are homogeneous in terms of chemical composition, have significantly better dissolution profile as compared to powder samples prepared by other techniques53, are suitable for direct compression54, can be used as inhalation powders directly52, or as fine solid components in ointments. In order to prepare the LPP by this method one needs to know the phase diagram of the system that includes all solute and solvent components.52 This task is time- and labour-consuming, since a phase diagram of an “API-solvent” binary system is to be considered. When a polymeric excipient is added, in order to form a solid dispersion of the crystalline drug in a polymer matrix, a phase diagram of the ternary system “API-solvent-excipient” must be considered.55-57 The problem of obtaining a co-crystal of two components is, generally speaking, even more challenging than that of obtaining a binary solid dispersion, since in the case of co-crystal the two components must not only precipitate as solid phases, but form together a periodic crystal structure. The few recent documented examples of obtaining co-crystals by freeze-drying described the cases when the solubilities of the two components of a co-crystal were high enough and well comparable with each other. If, however, the solubilities of the API and the co-former are very different (what is usually the case), then the problem of finding optimum conditions for their co-crystallization, in general, and on freeze-drying, in particular, is especially challenging. Low concentrations of dissolved components in frozen solutions can result in eruption of the material from the flasks/vials



The phase was first discovered in 200146, and then revisited in 201247, but could not be identified because of a low amount of the sample and, respectively, a poor quality of the PXRD pattern. ACS Paragon Plus Environment


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on drying. This problem can be solved by adding polymeric excipients to the two-component cocrystals, but the complexity of the phase diagram increases drastically. One of the main aims of preparing co-crystals of pharmaceutical co-crystals is to improve their dissolution profile. Co-crystals of poorly soluble active pharmaceutical ingredients (API) have been reported to have a higher solubility as compared with pure API.29,58-61 On the other hand, also a pure API, or its dispersion with a polymer, can be solubilized significantly, if prepared as fine powder. The micronization can be achieved not only by freeze-drying,62 but also by mechanical treatment63 liquid-assisted grinding (LAG)64, ball-milling17,65,66 or wet-milling.67-78 Up to now, LAG has been the main method of obtaining meloxicam co-crystals and improving meloxicam bioavailability.15,29,30,61,79 In this work we compare the dissolution dynamics of fine powders of pure meloxicam80, its co-crystal with succinic acid*, as well as of the dispersions of M and a M-SA co-crystal with polyethylenglycol prepared a) mechanically, b) by freeze-drying. Experimental Sample preparation The samples of M-SA co-crystals were obtained by several variants of freeze-drying: thin film freezing with subsequent freeze-drying (TFF+FD), spray freeze-drying (SFD), and conventional freeze-drying (cooling solutions in vials). Freeze-drying Freeze-drying was accomplished with a laboratory-scale freeze-dryer (NIIC SB RAS, Russia). Convection-enhanced Pirani gauges (275 Mini-Convectron® (Granville-Phillips®)) were used to monitor the chamber and condenser pressure. The shelf was equilibrated at -5/-20°C before the vials or drying trays were loaded and then placed under vacuum. Freeze-drying was carried out until pressure dropped to P < 14 mTorr (5 to 10 hours depending on samples). After that the shelf temperature was increased to 30°C, and held for 2 hours. The pressure in the freeze-dryer was subsequently increased to P=1 bar (ambient) by filling it with dry nitrogen. 1. Preparation of ultrafine meloxicam - succinic acid co-crystals by TFF+FD Meloxicam (175 mg) and succinic acid (30.5 mg) were dissolved on stirring at 70ºС in 17 ml of 1,4-dioxane in a transparent borosilicate glass vial (25 ml; Sci/Spec, B75540). Small amounts of solution were splashed onto a copper plate cooled to liquid nitrogen temperature, transparent pieces of frozen solution were separated manually (Figure S2) as described by Surovtsev et al.47 After that *

Succinic acid is one of the most common co-formers. Its co-crystals with many pharmaceuticals, in particular, with oxicams, are well-known7,8,15,29,30. Succinic acid is itself recognized as an active pharmaceutical ingredient. ACS Paragon Plus Environment

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the sample was ground in a mortar and placed onto a drying tray that was pre-cooled to the liquid nitrogen temperature. The tray was placed onto a shelf preliminary cooled to -5ºС and freeze-dried. 2. Preparation of ultrafine meloxicam - succinic acid co-crystals by SFD Meloxicam (175 mg) and succinic acid (30.5 mg) were dissolved in 17 ml of 1,4-dioxane on stirring at 70ºС in a transparent borosilicate glass vial (25 ml; Sci/Spec, B75540). The hot solution was sprayed using an atomizer (diameter of the capillary 0.4 mm, excessive pressure of the spraying gas equal to 1.5 bar) into a vessel with liquid nitrogen. The mixture of the solid phases that formed on cooling was placed onto a drying tray, that was pre-cooled to liquid nitrogen temperature. The tray was placed onto a shelf preliminary cooled to -5 ºС and then freeze-dried. 3. Preparation of ultrafine meloxicam - succinic acid co-crystals by conventional FD Meloxicam (326 mg) and succinic acid (54 mg) were dissolved in 34 ml of 1,4-dioxane on stirring at 70ºС in a transparent borosilicate glass vial (40 ml; Sci/Spec, B75540). The obtained solution (5.00 ml aliquots) was immediately put into vials (25 ml; Sci/Spec, B75525) preheated to 70°C. Freezing methods (Figure S3, Table S1): a) Vials were tightly closed with TFE caps and placed into a vessel with liquid nitrogen. b) Vials were tightly closed with TFE caps and frozen in a cryothermostat (KRYO-VT-05-02, TERMEX, Russia) at -50°C (30 min). c) Vials were placed onto a shelf preliminary cooled to -20ºС for 2 hours; Immediately after freezing all vials were placed onto a shelf that was preliminary cooled to 5°С / -20 ºС and after that freeze-dried (starting chamber pressure of 50 mTorr in all series). For the determination of cooling rates, type K thermocouple was placed in one vial in each series (“a” – “c” above), the junction being approximately in the middle of the sample in the vial. The temperatures in each of the samples were digitally recorded. The absolute temperature uncertainty was ± 0.2°C. 4. Preparation of ultrafine meloxicam - succinic acid co-crystals immobilized in the PEG matrix by conventional FD Meloxicam (326 mg), succinic acid (54 mg) and PEG-4k (1400 mg) were dissolved in 1,4dioxane (34 ml) on stirring at 70ºС. The solution (5.00 ml aliquots) was immediately put into 6 vials (25 ml; Sci/Spec, B75525) preheated to 70°C and then frozen in a cryothermostat (KRYO-VT-0502, TERMEX, Russia) at -50°C. Vials were placed onto a shelf preliminary cooled to -20 ºС and freeze-dried (starting chamber pressure of 200 mTorr). ACS Paragon Plus Environment


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For a comparison micronized samples of meloxicam were obtained by SFD, and those of meloxicam co-crystal with succinic acid - by ball-milling (BM) and liquid-assisted grinding (LAG) as described in Refs.15,29,30 (details are given in the ESI). Sample characterization Samples were characterized by a complex of experimental techniques, including scanning electron microscopy (SEM), specific surface area measurement using BET method (N2 adsorption/desorption), powder X-ray diffraction (PXRD), gas chromatography and massspectroscopy (GC+MS), dissolution tests using optical spectroscopy. Details are given in ESI. Results and discussion The solubility of meloxicam, M, in tert-butanol (the organic solvent which is most commonly used in freeze-drying) is too low (< 1 mg/ml; total solute ~0.1 wt %), to enable obtaining a M-SA cocrystal by freeze-drying. The melting points of almost all Class 3 residual solvents† are too low (below -70°C, see Table S2 for details), to make these solvents suitable for freeze-drying. Though solutions in these solvents could be solidified by using cryogenic technologies (TFF, SFD, SFL), it would be necessary to maintain the sample temperature below the solvent melting point. Therefore, condenser must be cooled by liquid nitrogen. At the same time, this contradicts another important condition: the critical temperature of primary drying should not be lower than -40°C, in order to allow for a reasonable drying time.81 The only Class 3 solvent with acceptable melting point (+18.6°C) and suitable solubilities of M and SA is DMSO. However, this solvent was also rejected after preliminary experiments because of the water condensation problem. During TFF or SFD, the water condensation from air at the surface of the liquid nitrogen (or at the samples) leads to the appearance of ice Ih. As a result, the melting temperature of the frozen solution decreases significantly,82 and the “DMSOwater” liquid inclusions remain entrapped within the frozen matrix. It is practically impossible to get rid of these inclusions on drying, and the quality of the freeze-dried powders obtained from DMSO is low. The samples of meloxicam obtained by SFD technique collapse during primary drying; the M-SA sample obtained by TFF+FD decomposes into the mixture of individual phases of M and SA. As a result, we selected 1,4-dioxane (the Class 2 residual solvent, what means that its use in pharmaceutical products is limited because of the inherent toxicity50). The values of M and SA solubilities in this solvent, the melting point of the pure solvent (+12°C), and the eutectic melting in the presence of ice Ih (-15.8°C83) were acceptable. See more details in ESI. Using dioxane as a solvent

†

Solvents that do not cause a human health hazard at levels normally accepted in pharmaceuticals ACS Paragon Plus Environment

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did not result in the contamination of the solid product by this compound. Tests of the residual 1,4dioxan level in our samples by GC+MS have given the value of 250 ppm, that is significantly lower than the allowed concentration limit (380 ppm)84. Varying the size of vials and decreasing the loads, so that to decrease the fill height and therefore the height of a cake, further reduces the residual level of 1,4-dioxan. The solubilities of M and SA both in water and in organic solvents differ very significantly. Therefore, one could expect that a co-crystal M-SA will be dissolved incongruently56 (Figure S4, а2). As soon as a liquid phase (solution) appears in the system, the co-crystal will decompose into two components, and the better soluble component (succinic acid) will be dissolved. The M-SA is destabilized when brought it contact with a solution of the stoichiometric M:SA ratio, i.e. the M-SA solubility curve does not cross the stoichiometric M:SA ratio line on the phase diagram of the “MSA-1.4-dioxane” ternary system56 (Figure S4, а2). Тhus, M-SA could be, in principle, obtained by crystallization from solutions with a non-stoichiometric excess of SA. However, for freeze-drying, one would use a stoichiometric M:SA solution, in order to increase the concentration of M present in solution. This imposes additional restrictions on the experimental protocol that must exclude the formation of a fluid phase (melting). A co-crystal could be obtained from a stoichiometric mixture of the M and SA components in the presence of a solvent only on the following conditions: 1.

A minimum amount of solvent is used (liquid-assisted grinding) (Figure S4, а2, I.).

2.

Maximum possible rate of cooling a solution is used. Otherwise, attempts to obtain a

M-SA co-crystal either on evaporation, or on cooling of solution will result in the precipitation of the poorly soluble component (М), or of a mixture of phases M and SA (Figure S4, а2, II.). Cooling solutions in vials (conventional freeze-drying) is usually characterized by relatively low cooling rates (~ 1°/sec).45,85 At the same time some rapid freezing technologies: spray freezedrying (SFD), spray freezing into liquid (SFL), and thin film freezing (TFF) are widely used in particle engineering, in particular, for the solubilization of poorly water-soluble APIs.45,85 The summary of methods, used for screening of M-SA co-crystallization, are given in Table S1 in ESI. The scanning electron microscopy (SEM) microphotographs of the samples obtained by three different techniques, namely, by TFF + FD, SFD, and LAG, are shown in Figure 1. The PXRD patterns are plotted in Figure 2. The samples obtained by TFF + FD, SFD and LAG contained pure M-SA co-crystal, whereas the precipitate taken after thawing of the frozen solution contained only pure meloxicam, while all the succinic acid remained in solution. The M-SA co-crystals were formed either on flash-freezing of the starting solution, or in the solid phase during the removal of solvent by sublimation.40 Unfortunately, we could not distinguish unambiguously between these two possibilities, since an in situ diffraction study of the crystallization process of a very diluted initial ACS Paragon Plus Environment


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solution (~ 1.1 wt %) was not technically feasible. Such studies were carried out earlier for significantly more concentrated solutions of glycine (5-30 wt %)47,51 or D,L-cysteine (11 wt %)86 that crystallized on freezing, or of paracetamol (5-25 масс %) that crystallized on subsequent freezedrying53,54. The M-SA co-crystal was prepared by TFF+FD as a white light fluffy powder with a very low bulk density (Figure S5). According to SEM data, these samples consisted of planar particles with linear dimensions of 0.5-2 μm and thickness less than 50 nm (Figure 1 a,b). In contrast to the sample of the same co-crystal obtained by LAG (Figure 1 e,f)15, the samples obtained by TFF+FD did not suffer from agglomeration. In contrast, M-SA co-crystal powders prepared by SFD, consisted of planar particles with linear dimensions of 0.2-1 μm (Figure 1 c,d) but prone to aggregation (100 μm – 4 mm) and electrostatic charging (Figure S6) what complicated a study of their properties. In general, the SFD powders usually consist of porous spherical agglomerates (up to 100 μm) of perforated flat sheets (linear dimensions 1-10 μm and thickness about 50-100 nm).52,87,88 In the case of obtaining a M-SA sample by SFD, however, the starting solutions have very low solute concentration (~1.1 wt %). The solid sample obtained by this technique therefore consisted of agglomerates that could not support their own weight and collapsed. The values of the specific surface area for M-SA samples obtained by TFF+FD, SFD and by LAG were 18±0.5 m2/g, 13±2 m2/g and 6±0.1 m2/g, respectively. For pure M the specific surface area was 13±0.3m2/g for the samples obtained by SFD, and 36±2 m2/g – by grinding. For a comparison, specific surface area of the starting meloxicam was 1.4±0.2 m2/g. The increase in the specific surface area correlated with the improved dissolution profile (Figure 3). Not only more meloxicam was released from the M-SA on dissolution as compared with pure M, but also the samples obtained by SFD dissolved much faster and gave higher meloxicam concentration in solution, than those obtained by LAG (Figure 3). This is an important improvement in view of the pharmaceutical applications of meloxicam, which has good permeability, but poor solubility (Class 2 BCS).89 TFF or SFD techniques are not well suitable for scaling up a process. Different variants of freezing of solutions in the vials are advantageous in this respect. In an earlier study by Jones et al.40 co-crystals of selected compounds have been obtained by freezing solutions in a flask in liquid nitrogen with the subsequent freeze-drying. In a recent study of obtaining co-crystals by freeze-drying “self-freezing” of solution on (un-controllable) decreasing pressure was used.41,42 The cooling rates in either of these studies were very high. We tested the applicability of the same techniques to our system. In particular, we were interested to find the maximum possible freezing temperatures for freezing solution in vials. We carried out a series of experiments with variable freezing rate. After a target temperature has been achieved, one vial from the whole series was broken, to extract a sample ACS Paragon Plus Environment

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of the frozen cakes. Visual inspection did not reveal any color gradient “white” – “yellow” from the side surface or the bottom of the vial to its center, even when using the lowest freezing rates (Figure S9). This gives evidence that no separate crystallization of components occurs under such conditions. This is further supported by X-ray powder diffraction data that correspond to pure M-SA phase (Figure 4). However, the powder was blown out of the vials on freeze-drying, even at lower sublimation rates (the temperature of the shelf -20°С and the pressure in the chamber > 200 mTorr.) (Figure 5a). It has been thus shown, that a) pure co-crystal phase can be obtained even on freezing under mild conditions achievable in most laboratory freeze-driers, but b) most of the product gets lost from the vial on drying because of low solute concentration. In order to suppress blowing the sample out of the vials, a commonly used technique is to add an excipient. None of the low-molecular weight excipients, which are usually used in freeze-drying as bulking agents/carriers (glycine, mannitol, sucrose, etc.)44,81,89 are sufficiently soluble in 1,4dioxane. Using 1,4-dioxane-water mixtures, in order to increase the solubility of an excipient, decreases the solubility of meloxicam even further, and is therefore not acceptable. Among most common polymers also used as bulking agents/carriers or for solubilization of poorly soluble APIs (BSA, PEG, PVP, etc.)44,91-93, we have selected polyethylene glycol, PEG 4000, which is well-soluble in 1,4-dioxane. The selected amount of PEG made it possible to increase the total solute content to 5 wt %. This has in fact helped to completely suppress the blowing-out of the sample (Figure 5b). Visual inspection of the sample obtained by freeze-drying of the M / SA / PEG solution in 1,4-dioxane revealed a stable freeze-dried cake lacking any signs of skin on the cake surface and without any collapsed inclusions near the bottom of the vial (surface area for M-SA/PEG sample was 6±0.3 m2/g). According to X-ray diffraction, the samples contained M-SA as the only crystalline phase that formed in M/SA binary system (Figure 4). Dissolution of the samples containing PEG was even faster than that of pure M-SA co-crystals obtained by TFF+FD (Figure 3). The solid dispersion is promising for instant release formulations of meloxicam, since all the meloxicam contained in it released after 7 minutes. Conclusions In the present work we have shown the possibility to obtain co-crystals of the components with strongly different water solubility (poorly soluble pharmaceutical organic compounds with wellsoluble co-formers) using several freezing protocols, including a “classical” variant of freeze-drying, which is most suitable for practical applications, namely freezing of solutions in vials at temperatures that are accessible in laboratory refrigerators / freeze-driers, without freezing in liquid nitrogen. The same technique can be used for obtaining solid dispersions of these co-crystals with well-soluble polymeric excipients for fast-release pharmaceutical formulations. ACS Paragon Plus Environment


Acknowledgements Financial support: Ministry of Science and High Education of Russian Federation.


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Figure captions Figure 1. The scanning electron microscopy (SEM) microphotographs of the samples obtained by three different techniques, namely, by thin-film freezing + freeze-drying (TFF + FD) (a, b), spray freezedrying (SFD) (с, d), and liquid-assisted grinding (LAG) (e, f). Figure 2. X-ray powder diffraction patterns: (a) starting succinic acid; (b) starting meloxicam; (с) precipitate taken after thawing of the frozen (TFF) M/SA solution; (d) X-ray powder diffraction pattern calculated for pure meloxicam based on single-crystal X-ray diffraction data (SEDZOQ0180); (e) Xray powder diffraction pattern calculated for a M-SA co-crystal based on single-crystal X-ray diffraction data (ENICOU61), (f) M-SA obtained by TFF+FD; (g) M-SA obtained by SFD; (h) M-SA obtained by LAG. Figure 3. Dissolution profiles of: (a) M-SA co-crystal in PEG matrix, obtained by conventional freeze-drying of solutions in vials; (b) M-SA obtained by TFF+FD; (c) M powder obtained by SFD; (d) M-SA obtained by LAG; (e) ball-milled M powder. Figure 4. X-ray powder diffraction patterns: (a) PEG-4k sample, solution in 1,4-dioxane frozen in a vial and freeze-dried; (b) M-SA in PEG-4k matrix; (c) and (d) M-SA obtained by conventional freeze-drying in a vial, powder residue and the portion of the sample that was blown out from a vial, respectively; (e) M-SA obtained by TFF+FD. Figure 5. A. Blowing out of the M-SA co-crystal samples during freeze-drying even in the case of low drying rates (shelf temperature: -20°С). B. Preventing the blowing out of the samples during freeze-drying (using PEG as a bulking agent).



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For Table of Contens Use Only Cryosynthesis of co-crystals of poorly water-soluble pharmaceutical compounds and their solid dispersions with polymers. “Meloxicam - succinic acid” system as a case study. Andrey G. Ogienko, Svetlana A. Myz, Anna A. Ogienko, Andrey A. Nefedov, Andrey S. Stoporev, Maxim S. Mel’gunov, Alexander S. Yunoshev, Tatyana P. Shakhtshneider, Vladimir V. Boldyrev, Elena V. Boldyreva* This work illustrates the potential of freeze-drying for obtaining pharmaceutical сo-crystals from the components that differ drastically in their solubilities.

Supporting Information. Additional details of the experimental procedure: preparation of reference samples (meloxicam succinic acid co-crystals obtained by solvent-drop grinding; ultrafine meloxicam prepared by SFD; micronized meloxicam prepared by ball-milling), sample characterization (PXRD, SEM, GC-MS, specific surface area determination, dissolution studies). Additional figures and tables: Preparation SFD powder sample for XRD experiments in the TTK 450 sample holder (fill depth 0.3 mm); Samples of a frozen solution of meloxicam and succinic acid in 1,4-dioxane obtained by thin film freezing (TFF); Estimated cooling rates corresponding to different freezing methods; Brief description of methods used for screening of M-SA co-crystallization; Melting points of Class 3 residual solvents and tested succinic acid / meloxicam solubility in some solvents; Isothermal sections and projections of the “API – co-former - solvent” ternary system; Comparison of the bulk volumes


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of the same amount (0.222 g) of ultrafine M-SA, obtained by TFF+FD and the starting substances of meloxicam and succinic acid (right) in 30 ml vials; Illustration on handling difficulties due to aggregation and electrostatic charging of ultrafine M-SA, obtained by SFD; Comparison of the bulk volumes of the same amount (0.290 g) of ultrafine meloxicam, obtained by SFD and the starting substance of meloxicam (right) in 30 ml vials; SEM images of the ultrafine meloxicam obtained by spray freeze-drying and micronized meloxicam recrystallized from 1,4-dioxane; Illustration that visual inspection did not reveal any color gradient “white” – “yellow” from the side surface or the bottom of the vial to its enter, even if the lowest freezing rates were used; SEM images of M-SA samples obtained by conventional freeze-drying: pure M-SA (flying the sample off from vials) and M-SA in PEG matrix; Surface area and pore volume-size distribution measurement; Residual 1,4-dioxan level determination; Dissolution studies; Additional References.



Figure 1. The scanning electron microscopy (SEM) microphotographs of the samples obtained by three different techniques, namely, by thin-film freezing + freeze-drying (TFF + FD) (a, b), spray freeze-drying (SFD) (с, d), and liquid-assisted grinding (LAG) (e, f).


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Figure 2. X-ray powder diffraction patterns: (a) starting succinic acid; (b) starting meloxicam; (с) precipitate taken after thawing of the frozen (TFF) M/SA solution; (d) X-ray powder diffraction pattern calculated for pure meloxicam based on single-crystal X-ray diffraction data (SEDZOQ0180); (e) X-ray powder diffraction pattern calculated for a M-SA co-crystal based on single-crystal X-ray diffraction data (ENICOU61), (f) M-SA obtained by TFF+FD; (g) M-SA obtained by SFD; (h) M-SA obtained by LAG. 349x585mm (72 x 72 DPI)



Figure 3. Dissolution profiles of: (a) M-SA co-crystal in PEG matrix, obtained by conventional freeze-drying of solutions in vials; (b) Figure 3. M-SA obtained by TFF+FD; (c) M powder obtained by SFD; (d) M-SA obtained by LAG; (e) ball-milled M powder. 928x330mm (72 x 72 DPI)


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Figure 4. X-ray powder diffraction patterns: (a) PEG-4k sample, solution in 1,4-dioxane frozen in a vial and freeze-dried; (b) M-SA in PEG-4k matrix; (c) and (d) M-SA obtained by convenient freeze-drying in a vial, powder residue and the portion of the sample that was blown out from a vial, respectively; (e) M-SA obtained by TFF+FD. 349x447mm (72 x 72 DPI)



Figure 5. A. Blowing out of the M-SA co-crystal samples during freeze-drying even in the case of low drying rates (shelf temperature: -20°С).B. Preventing the blowing out of the samples during freeze-drying (using PEG as a bulking agent). 166x230mm (300 x 300 DPI)


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Cryosynthesis of co-crystals of poorly water-soluble pharmaceutical

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