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Discovery strategy leads to the first melt-castable cocrystal based on an energetic oxidizing salt†
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Publication date (Electronic, pub):
10 October 2022
Publication date (Electronic, collection):
26 October 2022
Journal:
Chemical Science
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The Royal Society of Chemistry
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Abstract
Cocrystallization is a synthetic method employed across fields to improve functional materials while preserving properties inherent to the molecules/ions involved. However, there is no guarantee that cocrystals will demonstrate improved properties relative to the constituent materials. Oxygen balance, which is closely correlated to the performance of energetic materials, is an exception in that this attribute may be targetted with certainty. The combination of energetic oxidizing salts with small molecules presents a seemingly straightforward path to energetic materials with desirable performance properties. Unfortunately no general approach for the cocrystallization of salts and small molecules (salt cocrystallization) has yet emerged. Presented here is such an approach, focussing on ammonium salts, and applied to the energetic oxidizing salt ammonium dinitramide to achieve a melt-castable energetic material. Though focused on ammonium salts, this salt cocrystallization paradigm is a general approach that may be extended to other ions.
Abstract
An ammonium salt cocrystallization paradigm is developed and applied to the energetic oxidizing salt ammonium dinitramide. The approach presented here is generally applicable in the development of ion-specific salt cocrystallization strategies.
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Most cited references38
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The Cambridge Structural Database
Colin Groom, Ian Bruno, Matthew P. Lightfoot … (2016)
This paper is the definitive article describing the creation, maintenance, information content and availability of the Cambridge Structural Database (CSD), the world’s repository of small molecule crystal structures.
- Record: found
- Abstract: not found
- Article: not found
Supramolecular Synthons in Crystal Engineering—A New Organic Synthesis
Gautam Desiraju (1995)
- Record: found
- Abstract: found
- Article: not found
Pharmaceutical Cocrystals and Their Physicochemical Properties
Nate Schultheiss, Ann Newman (2009)
I Introduction A Common Pharmaceutical Strategies for Altering API Properties It is well-known that crystalline materials obtain their fundamental physical properties from the molecular arrangement within the solid, and altering the placement and/or interactions between these molecules can, and usually does, have a direct impact on the properties of the particular solid.(1) Currently, solid-state chemists call upon a variety of different strategies when attempting to alter the chemical and physical solid-state properties of APIs, namely, the formation of salts, polymorphs, hydrates, solvates, and cocrystals, as illustrated in Figure 1. Figure 1 Pictures displaying the more common solid-state strategies and their respected components. Currently, salt formation is one of the primary solid-state approaches used to modify the physical properties of APIs, and it is estimated that over half of the medicines on the market are administered as salts.(2) However, a major limitation within this approach is that the API must possess a suitable (basic or acidic) ionizable site. In comparison, cocrystals (multicomponent assemblies held together by freely reversible, noncovalent interactions) offer a different pathway, where any API regardless of acidic, basic, or ionizable groups, could potentially be cocrystallized. This aspect helps complement existing methods by reintroducing molecules that had limited pharmaceutical profiles based on their nonionizable functional groups. In addition, the number of potential nontoxic cocrystal formers (or coformers) that can be incorporated into a cocrystalline reaction is numerous.(3) It should be made clear that no one particular strategy offers a solution for property enhancement of all APIs. Each API must be examined and evaluated on a case-by-case basis in terms of molecular structure and desired final properties. For this purpose, general guidelines for rational cocrystal design through supramolecular synthesis will be highlighted first. B Cocrystals and Salts To date, a universal and agreeable definition of what constitutes a cocrystal is still unavailable. Within the academic literature, various parameters have been applied to the definition of what is and is not considered a cocrystal (Table 1); however, one broad commonality that is agreed upon is that all cocrystals are crystalline materials comprised of at least two different components (or commonly called multicomponent crystals). Now, one’s opinion as to what constitutes a “component” can be dramatically different, for example, solid, liquid, or gas and/or neutral or ionic species, etc., and this is usually where the differences in definitions arise. Furthermore, the use of “pharmaceutical cocrystal” is commonplace and usually applied when an API is one of the molecules in the multicomponent crystal. Table 1 Definitions of a Cocrystal author definition of a cocrystal ref Stahly, G. P. “a molecular complex that contains two or more different molecules in the same crystal lattice” (4) Nangia, A. “multi-component solid-state assemblies of two or more compounds held together by any type or combination of intermolecular interactions” (5) Childs, S. L. “crystalline material made up of two or more components, usually in a stoichiometric ratio, each component being an atom, ionic compound, or molecule” (6) Aakeröy, C. B. “compounds constructed from discrete neutral molecular species...all solids containing ions, including complex transition-metal ions, are excluded” “made from reactants that are solids at ambient conditions” “structurally homogeneous crystalline material that contains two or more neutral building blocks that are present in definite stoichiometric amounts” (7) Bond, A. “synonym for multi-component molecular crystal” (8) Jones, W. “a crystalline complex of two or more neutral molecular constituents bound together in the crystal lattice through noncovalent interactions, often including hydrogen bonding” (9) Zaworotko, M. J. “are formed between a molecular or ionic API and a co-crystal former that is a solid under ambient conditions” (10) Even though there are limitations with the cocrystal definitions currently found in the literature, we do not see it necessary to complicate the existing debate by generating yet another definition for what constitutes a cocrystal. In this review, the cocrystalline examples presented herein will possess the following criteria: (1) An API, neutral (example 1, Figure 2), or ionic form (example 2, Figure 2, or a zwitterion), along with a neutral coformer, held together through noncovalent, freely reversible interactions, (2) a coformer, which may or may not be pharmaceutically acceptable, (3) and at least one measured physicochemical property. A pictorial description of possible multicomponent systems, including cocrystals,(11) salt cocrystals, 12,13 and salts along with their respective hydrates and solvates are displayed in Figure 2. When necessary for property or structural comparison, examples of pharmaceutical salts (example 3, Figure 2) will be introduced and discussed. The examples used throughout the paper are representative of the literature reported for the physicochemical properties measured for pharmaceutical cocrystals, but it is not an exhaustive list of all the cocrystal studies available. Figure 2 Possible multicomponent systems: cocrystals, salt cocrystals, and salts along with their respective solvate/hydrate forms. C Crystal Engineering of Pharmaceutical Cocrystals The number of publications and reviews detailing the topics of crystal engineering and supramolecular synthesis of API-based cocrystals is extensive and continuing to grow.(14) More specifically, researchers usually highlight themes pertaining to functional group compatibility (synthons), for example, acid/N-heterocycle, acid/amide, phenol/N-heterocycle, and/or cocrystal growth strategies such as evaporation,(15) solid-state grinding,(16) sonication,(17) and melting.(18) To complement these topics, we would like to briefly mention the initial steps that should be considered (before a reaction is ever conducted!) when attempting to maximize the experimental effectiveness of generating cocrystalline materials. In the beginning, an evaluation of the API should be carried out, including but not limited to, number and arrangement of hydrogen bond donors and acceptors, 7,19 salt forming ability (pK a’s),(20) conformational flexibility, and solubility requirements.(21) Usually APIs that are rigid, highly symmetrical, possess strong nonbonded interactions, and low molecular weight are more apt to cocrystallize with additional components (coformers or counter-molecules).(4) Frequently, suitable coformers are selected based on hydrogen bonding rules,(22) probable molecular recognition events,(23) and toxicological profiles; 2a,24 however, one should not be limited to just these criteria because cocrystals could easily be missed. Finally, as mentioned above, a variety of methods exist for preparing cocrystals. To date, predicting whether or not a cocrystallization reaction will be successful is not yet possible,(25) and thus reactions must be carried out experimentally under varied conditions with different techniques to find available cocrystals. D Cocrystal Characterization Single crystal X-ray diffraction is the preferred characterization technique in determining whether a cocrystalline material has been generated; however, suitable X-ray quality crystals cannot always be produced. Additionally, even if single crystals can be grown of sufficient size and quality, the exact location of the hydrogen atom (determination if proton-transfer has occurred from the acid to the base or not) may be ambiguous. 20c,26 Thus, it is advantageous to utilize a variety of solid-state, spectroscopic techniques (Raman, infrared, and solid-state NMR) when attempting to characterize potentially new cocrystalline materials.(27) Such an exercise was carried out when single-crystal X-ray crystallography and 15N solid-state cross-polarization magic angle spinning (CPMAS) NMR spectroscopy were used to complement one another in the determination of hydrogen bonding interactions and the extent of proton-transfer between a heterocyclic-containing API and a variety of dicarboxylic acids.(28) Three acid−base complexes were obtained and characterized: a sesquisuccinate, a dimalonate, and a dimaleate. Through single-crystal X-ray analysis, measured hydrogen bond distances were used to characterize the materials as one cocrystal (sesquisuccinate), one mixed ionic and zwitterionic complex (dimalonate), and one disalt (dimaleate). These results were confirmed by comparing the 15N chemical shifts of each species to those of the free base. Small shifts, in comparison to the free base, were observed for the sesquisuccinate cocrystal, while the largest shifts, due to complete protonation, were seen from the dimaleate salt. In addition, short contact time CPMAS NMR experiments were used to further characterize the dimalonate and dimaleate complexes as a mixed ionic species and a disalt. For example, if a nitrogen atom had a proton attached to it, then a signal would appear; thus the disalt (dimaleate) displayed two additional peaks in comparison to the free base, while the mixed ionic species (dimalonate) only showed one new peak. The results from the 15N solid-state CPMAS NMR spectroscopy along with single-crystal X-ray crystallography proved sufficient to successfully identify each new form as either a cocrystal, salt, or mixed ionic complex. Infrared spectroscopy can be a very powerful tool in detecting cocrystal formation, especially when a carboxylic acid is used as a coformer and/or when a neutral O−H···N hydrogen bond is formed between an acid and a base. Distinct differences, within the IR spectra, can be observed between a neutral carboxylic acid moiety and a carboxylate anion. A neutral carboxylate (-COOH) displays a strong C=O stretching band around 1700 cm−1 and a weaker C−O stretch around 1200 cm−1, while a carboxylate anion (-COO−), due to resonance, displays a single C−O stretch in the fingerprint region of 1000−1400 cm−1. Additionally, if a neutral intermolecular O−H···N hydrogen bond has formed between the components, then two broad stretches around 2450 and 1950 cm−1 will be observed.(29) Observations about the state of the carboxylic moiety (neutral or ionic) can also be verified through measuring the C−O and C=O bond distances from the single-crystal X-ray data. A typical C=O bond distance is around 1.2 Å, while the C−O bond distance is around 1.3 Å; however, if deprotonation has occurred then the resonance stabilized C−O bond distances will be very similar. 20c,30 Outlined above are a number of different characterization techniques used to help distinguish between cocrystals and salts, and it should be noted that in some cases differentiation between the two may be difficult.(20c) It should also be pointed out that although salts and cocrystals often possess different properties (see sections on stability () and solubility ()), these issues from a development standpoint may not be influential as long as the process can be monitored and closely controlled. However, for intellectual property (IP) rights and regulatory issues, differentiating between a cocrystal and a salt can be important, as discussed in . II Physicochemical Property Review The physical and chemical properties of a cocrystal need to be investigated in the same manner as any other solid form in order to determine developability into a marketed dosage form.(31) Physicochemical properties, such as crystallinity, melting point, solubility, dissolution, and stability, are important when moving a new compound, such as a cocrystal, through early development. The information from these studies can be used to prioritize the available forms, and a flowchart can help organize the process for solid form selection. An example of a flowchart that could be used to choose the best cocrystal candidate is given in Figure 3. It combines a number of properties inherent to drug development; however, it should be used as a guide only since every compound will have its own challenges, and the properties in the flowchart will be unique to the situation at hand. Figure 3 Example flowchart for choosing a cocrystal candidate. The primary focus of this article is centered on highlighting cases where the physicochemical properties of an API have been adjusted through the formation of API-based cocrystals. The properties and questions are Melting point: Does the thermal behavior (melting point) of a cocrystal change with respect to the individual components and can the melting points be estimated within a series of cocrystals? Stability: Can physical and chemical stability be enhanced upon cocrystallization of an API? Solubility: Can the solubility of an API be altered by modifying it into a cocrystal? Dissolution: Are dissolution rates improved by cocrystalline compounds in comparison to the individual APIs? Bioavailability: Can the bioavailability of an API be improved using cocrystals? Related topics, such as scale-up, polymorphism, intellectual property, and lifecycle management are also discussed for the development of pharmaceutical cocrystals. A Melting Point The melting point is a fundamental physical property, which is determined by the temperature at which the solid phase is at equilibrium with the liquid phase. Since melting point is a thermodynamic process where the free energy of transition is equal to zero, the value is determined by the ratio of change in the enthalpy of fusion over the change in the entropy of fusion.(32) If available, differential scanning calorimetry (DSC) is the preferred technique for obtaining comprehensive melting point data, over a standard melting point apparatus or Kofler method, because additional thermal data such as the enthalpy of fusion can be determined. For example, the melting point and heat of fusion, both determined from DSC, are necessary when attempting to characterize a polymorphic pair of compounds as monotropic or enantiotropic.(33) It is standard practice to determine the melting point of a compound as a means of characterization or purity identification; however, within pharmaceutical sciences, the melting point is also very valuable due to its correlations to aqueous solubility and vapor pressure.(34) In fact, the melting point has been directly correlated to the Log of solubility, although assumptions pertaining to the entropy of fusion had to be drawn.(35) Thus, being able to determine the melting point of a particular API before it was synthesized would be very beneficial in order to tailor its aqueous solubility toward a particular function. Unfortunately, correlations relating chemical structure directly to melting point data remain elusive.(36) Given the number of factors contributing to the melting point of a crystalline solid including, but not limited to, the molecular arrangement within the crystal lattice, molecular symmetry, intermolecular interactions, and conformational degrees of freedom for a molecule, one clearly sees the difficulties in attempting to draw strict comparisons from molecular structure to crystalline lattice energy to melting point. The situation only becomes more complex when observing multicomponent systems because each component has its own characteristic properties and those can influence the environment (and intermolecular interactions) around its neighbors. In this section we will examine the thermal behavior of cocrystals in which one component is an API, although findings and trends should be translatable to all cocrystalline materials. One literature example compares the melting points of 10 cocrystals to the API AMG517 and their respective coformers.(37) Each of the cocrystals displayed a melting point that fell between the melting point of AMG517 and their coformer. A plot was generated using the melting points of the cocrystals and coformers, which displayed a direct proportionality between the two (Figure 4). A correlation coefficient of 0.7849 was determined, meaning that 78% of the variability of melting point of the cocrystal can be attributed to the variability of the coformers melting point. These data show that within the set of AMG517 cocrystals the melting point can typically be tuned according to which coformer is chosen; for example, if a higher melting cocrystal is desired, then a higher melting coformer should be selected and vice versa. Figure 4 Melting points of AMG517 cocrystals and their respected coformers (left); melting onset of coformer versus cocrystal (right). Modified table and graphic from ref (37). Copyright 2008 American Chemical Society. We compiled a larger survey based on reported cocrystal melting points, and these were compared with the melting points of the coformer and API. The purpose was to determine if any correlation can be drawn, with regard to where the melting point of the cocrystal falls: higher, lower, or in between that of the API and coformer. The data are summarized in Table 2. It should be noted that this exercise is not taking into account stoichiometry of components, solvation or hydration, polymorphism, and/or types of intermolecular interactions present within the crystalline lattice. Table 2 Melting Points of APIs, Coformers, and Their Respective Cocrystals APIa API MPb (°C) coformer coformer MP (°C) cocrystal MP (°C) rangec ref AMG517 230 (37) AMG517 trans-cinnamic acid 133 204 M AMG517 2,5-dihydroxybenzoic acid 205 229 M AMG517 2-hydroxybenzoic acid 61 130 M AMG517 glutaric acid 97 153 M AMG517 glycolic acid 78 141 M AMG517 sorbic acid 134 150 M AMG517 trans-2-hexanoic acid 34 127 M AMG517 l-(+)-lactic acid 46 138 M AMG517 benzoic acid 122 146 M AMG517 l-(+)-tartaric acid 171 198 M aspirin 133−135 (40) aspirin 4,4′-bipyridine 111−114 91−96 L carbamazepine 190−192 (21b) carbamazepine succinic acid 187 189 M carbamazepine benzoic acid 122 113 L carbamazepine ketoglutaric acid, Form A 115 140 M carbamazepine ketoglutaric acid, Form B 115 134 M carbamazepine maleic acid 137 158 M carbamazepine glutaric acid 98 125 M carbamazepine malonic acid, Form A 136 143 M carbamazepine oxalic acid 189 158 L carbamazepine adipic acid 152 137 L carbamazepine (+)-camphoric acid 186 156 L carbamazepine 4-hydroxybenzoic acid, Form A 213 172 L carbamazepine 4-hydroxybenzoic acid, Form C 213 170 L carbamazepine salicylic acid 159 159 carbamazepine 1-hydroxy-2-naphthoic acid 192 174 L carbamazepine dl-tartaric acid, Form A 205 170 L carbamazepine l-tartaric acid 169 160 L carbamazepine glycolic acid 149 139 L carbamazepine fumaric acid, Form B 287 189 L carbamazepine saccharin 225−227 174 L carbamazepine nicotinamide 128 151−161 M (38) carbamazepine benzoquinone 113−115 170 M carbamazepine terephthalaldehyde 114−116 124 M carbamazepine trimesic acid >300 278 (dec) M carbamazepine 5-nitroisophthalic acid 259−261 190 (dec) chlorzoxazone 192 (74) chlorzoxazone 2,4-dihydroxybenozoic acid, Form 1 213 179 L chlorzoxazone 2,4-dihydroxybenozoic acid, Form 1I 213 177 L chlorzoxazone 4-hydroxybenzoic acid 213-214 182 L ethyl-paraben 116 (39) ethyl-paraben nicotinamide 128 107 L flurbiprofen 113−114 (40) flurbiprofen 4,4′-bipyridine 111−114 155−160 H flurbiprofen trans-1,2-bis(4-pyridyl)ethylene 150−153 153−158 H fluoxetine HCl 157 (12) fluoxetine HCl benzoic acid 122 132 M fluoxetine HCl succinic acid 185−187 134 L fluoxetine HCl fumaric acid ∼287 161 M ibuprofen 77−78 (40) ibuprofen 4,4′-bipyridine 111−114 117−120 H indomethacin 162 (46) indomethacin saccharin 225−227 220 M norfloxacin 221 (41) norfloxacin isonicotinamide 155−157 180−185 M Pfizer 1 167 (28) Pfizer 1 succinic acid 185−187 143 L piroxicam 198−200 (64) piroxicam saccharin 225−227 220 M Purdue Pharma 1 206 (48) Purdue Pharma 1 glutaric acid 98 142 M a API, active pharmaceutical ingredient. b MP, melting point. c Range: cocrystal has H-higher melting points than API and coformer, M-melting point in between that of the API and coformer, L-lower melting point than API or coformer. Within the survey 50 cocrystalline samples were analyzed; 26/50 (51%) cocrystals had melting points between those of the API and coformer, while 19/50 (39%) were lower than either the API or coformer, only 3/50 (6%) were higher, and 2/50 (4%) had the same melting point as either the API or coformer. These statistics clearly show that the melting point of an API can be altered through forming cocrystals, and the outcome will usually be a product having a melting point that is in between that of the API and coformer or lower than the API or coformer. Thus, if a lower melting solid is necessary and covalent modifications to the API cannot be achieved, then cocrystallizing the API is a viable pathway. Within a homologous set of cocrystals (either the API or coformer is kept constant), where single crystal X-ray structures have been determined, comparisons could potentially be drawn between the intermolecular interactions and/or crystal packing existing within the lattice and the thermal behavior of the sample. This knowledge could be beneficial when attempting to determine the behavior of a particular material from its three-dimensional structure. In one example, a set of dipyridyl coformers are cocrystallized with ibuprofen, flurbiprofen, and aspirin producing four cocrystals: (ibuprofen)2(4,4′-bipyridine), (flurbiprofen)2(4,4′-bipyridine), (flurbiprofen)2(trans-1,2-bis(4-pyridyl)ethylene), and (aspirin)2(4,4′-bipyridine).(40) In all cases the compounds crystallize in a 2:1 API/coformer ratio through heteromeric O−H···N hydrogen bonds; however, the overall packing arrangements of the 2:1 supermolecules are different. The first three examples listed all take on a herringbone packing arrangement and have melting points higher than either the API or coformer, while the last example is a channel structure and possess a melting point considerably lower than either of the two reactants. Although this study is on a small number of samples, it shows the impact that crystal packing has on physical properties such as melting point. As mentioned earlier, correlations have been drawn between a compound’s melting point and its Log of solubility; however, the literature remains sparse when making comparisons to cocrystals. Only one study was found where cocrystals had their melting points and aqueous solubilities determined and compared. In the AMG517 study, the authors note that after a correlation analysis of the solubility parameters, the highest interdependence was the Log of solubility (Log S max) versus the melting point.(37) A correlation plot of Log S max versus cocrystal melting point, of the nine AMG517 cocrystals, indicated a 55% correlation of the variability in Log S max to variability in melting point of the cocrystal (Figure 5). This study, albeit on a homologous set of cocrystals, provides a foundation for attempting to compare the factors influencing a cocrystals melting point and its solubility. Figure 5 Solubility and Log S max values for AMG517 cocrystals (left); S max as a function of cocrystal melting point (right). Modified table and graphic from ref (37). Copyright 2008 American Chemical Society. Recently, a second cocrystallization study was conducted on a series of molecules with structures similar to AMG-517 along with a number of structurally diverse coformers.(42) Comparisons were made between the melting points of the cocrystals and coformers as well as between the melting points and the Log solubility values. The conclusions showed low correlations between the melting points of the cocrystals to the coformers and no correlation between the melting points of the cocrystals and the Log solubility. These findings clearly stress the difficulties when attempting to draw lines between series of molecules with different structures, especially as it pertains to solubility and melting point. Melting point is an important consideration during development. High melting points are usually desirable, but may contribute to poor solubility and are as troublesome as low melting points, which can hinder processing, drying, and stability. Correlation of melting points with other development parameters is an ongoing area of study, and the multicomponent nature of the cocrystals will add another level of complexity to these analyses. B Stability Stability is a heavily studied parameter during the development of a new chemical entity. Different types of stability need to be considered depending on the structure and characteristics of the molecule. Chemical and physical stability data are commonly obtained at accelerated stability conditions to determine developability and shelf life.(43) Water uptake is included from a handling and packaging point of view. The amount of water present can also lead to form changes, degradation, and worse if the effect of the water uptake is not investigated early in the process.(44) Thermal stress studies are also incorporated, and extra work may be warranted for hydrates or thermally labile materials. In the case of cocrystals and salts, solution stability may be a factor due to dissociation of the material resulting in precipitation of the less soluble parent compound or a less soluble form (such as a hydrate in aqueous media). This section will review a variety of stability data reported for cocrystals. 1 Relative Humidity Stress As with other solid forms, changes over a wide relative humidity (RH) range are a key consideration when developing a cocrystal. 44,45 Automated moisture sorption/desorption studies are commonly performed to determine problem areas and to provide direction for more detailed studies when the need arises. X-ray powder diffraction (XRPD) data collected on the solid at the end of the moisture balance experiment provides information on the final form, but not necessarily on any form conversions that may have occurred during the experiment. Significant moisture uptake during the course of the experiment may warrant longer exposure at a specific relative humidity using a relative humidity chamber and subsequent analysis of the sample after equilibration. Limited water sorption/desorption data were found in the literature for cocrystals. One example for a 1:1 indomethacin/saccharin cocrystal showed minimal uptake ( 1000 μm.(54) Samples were analyzed out to 120 min. The study focused on the initial rate of dissolution, which has been correlated to increased bioavailability for carbamazepine.(62) As expected, faster initial dissolution was observed with the smaller particles. Dissolution rates for sieve fractions >500 μm slowed to the point where carbamazepine concentrations were significantly lower after 2 h than the smaller particles. Sieved fractions >500 μm were less than 50% dissolved after 60 min; however, fractions 300.00 lamivudine free base 70.00 salt 10.56 risperidone free base 300 mg/mL for the various salts. Eight of the 10 salts exhibited a higher solubility than the free base, one was lower than the free base (lamivudine), and one (amlodipine) could not be measured due to hygroscopicity issues. It was interesting to note that the solution pH of the saccharin cocrystal was much lower (3.27) than the salts (5.25−6.25). A follow-up study compared calculated solubility values for salts and cocrystals formed with saccharin.(66) The thermodynamic solubility product (K sp) was calculated for the saccharin cocrystal (piroxicam) and the nine saccharinate salts based on one solubility value at a known pH and the pK of each component reported in the literature. The calculations showed that in water, salts can form for all 11 compounds in the study including piroxicam which formed a cocrystal. It was suggested that piroxicam was isolated as a cocrystal due to the shift in pK values when chloroform or ethanol solutions were used for crystallization. On the basis of the calculations, the general conclusion that the saccharinate salts were more soluble than the cocrystal was justified despite the pH differences. It was also noted that cocrystal solubility needs to take into account a revised definition of the solubility product as well as any possible complexation in solution and underlying factors related to both solid-state and solution chemistry. Solubility is a very important parameter to obtain during development of a new compound. As expected, the limited examples in this section show that solubility may be improved using cocrystals, but not in all cases. For a poorly soluble compound, especially if it does not have ionizable groups, it is worth trying cocrystals to see if an improvement can be obtained. In the case of cocrystals versus salts, there appears to be a trend that salts may offer a greater solubility advantage, as shown with limited data in Table 5, but more work needs to be performed to determine if this is a general trend. Solubility measurements of cocrystals will continue to present interesting challenges for pharmaceutical scientists. D Intrinsic Dissolution Intrinsic dissolution measures the rate of dissolution without the effect of particle size. This is accomplished by pressing a disk or pellet, commonly using a Woods apparatus in a dissolution vessel.(67) Solution concentration is measured over time to determine the dissolution rate (in mg/cm2·min). The disk needs to remain intact during the experiment, so compression pressures may be critical for poorly compressible powders. It is also important that there is no form change upon pressing the pellet or during the dissolution study. XRPD data can be obtained on the initial disk and the remaining disk after completion of the experiment to determine any major form changes that may affect the dissolution data. There are a limited number of intrinsic dissolution studies on cocrystals. Data for the glutaric acid cocrystal of 2-[4-(4-chloro-2-fluorphenoxy)phenyl]pyrimidine-4-carboxamide(48) were collected in water over 90 min and showed that the cocrystal dissolution was approximately 18 times faster than the parent compound. XRPD of the remaining solid showed mainly the glutaric acid cocrystal, with only minor peaks for the parent material, indicating that the results were not skewed by significant form changes over the course of the experiment. The intrinsic dissolution rates for fluoxetine HCl cocrystals were also measured in water, Figure 8.(12) The dissolution of the 2:1 fluoxetine HCl/succinic acid cocrystal was too fast to measure an accurate value for the dissolution rate, but a 3−fold increase over fluoxetine HCl was estimated based on early time points. The 1:1 fluoxetine HCl/benzoic acid cocrystal was roughly half-that of the API and the 2:1 fluoxetine HCl/fumaric acid cocrystal was approximately the same as that of the API. These results show that cocrystals can enhance the dissolution rate, but can also show no improvement or a slower dissolution rate. It was interesting to note that the aqueous solubility of the guest molecule appears to correlate with the aqueous dissolution rates of the corresponding cocrystal, with benzoic acid being the least soluble (0.34 g/100 g), fumaric acid being intermediate in solubility (0.61 g/100 g), and succinic acid being the most soluble (7.5 g/100 g). Other examples will be needed to determine if this is a general trend or specific to this system. In a third study, measurements were obtained on 1:1 exemestane/maleic acid and 1:1 megestrol acetate/saccharin cocrystals in FaSIF.(63) The 1:1 exemestane/maleic acid cocrystal showed essentially the same dissolution rate as the exemestane alone; however, analysis of the remaining solid material showed a conversion to exemestane during the experiment. The 1:1 megestrol acetate/saccharin cocrystal was 3−4 times higher than megestrol acetate, but there were significant variations in the data. Analysis of the remaining solid showed only a small amount of conversion to megestrol acetate. These data show that the initial dissolution rate of megestrol acetate was improved by using the cocrystal. As discussed for solubility and solution stability, intrinsic dissolution is an important parameter to investigate, but it may become more complicated with cocrystals. Various factors need to be considered and extra experiments may be needed to correctly obtain and interpret intrinsic dissolution data on cocrystals. E Bioavailability Bioavailability is a measurement of the rate and extent of the active drug that reaches systemic circulation.(68) Animal bioavailability is an important parameter to consider when preparing new forms of a compound, and studies can be set up in a number of different ways to obtain specific information for development. Species for animal studies can include rodents, rabbits, dogs, pigs, and primates. These studies are usually performed during early development and can be small studies (4−6 animals) to determine pharmacokinetic data quickly on a new form. Usually the same animals are used for all forms/formulations with a washout period, typically, a week in length, between the doses. This gives a direct comparison within the same animals for all the materials in the study. A study with both the parent material and the cocrystal will give a direct assessment of bioavailabiliy improvements due to the cocrystal. In a relative or comparative bioavailability study, the amount of drug in the blood is measured after oral administration of the original form and then the cocrystal. Blood samples are taken after dosing to investigate blood levels over time. It is important to note that the materials used in the study need to be formulated in the same way if a direct comparison is desired. Most dosing is done orally and formulation possibilities include powder in a capsule, powder and excipient in a capsule, or liquid formulations (solutions or suspensions). It is important to differentiate between solutions and suspensions since dissolution of the solid in a solution could significantly improve bioavailability. For suspensions it is helpful to know how much of the compound may actually be dissolved in order to determine how that may affect the results. Absolute bioavailability includes not only the cocrystal formulation, but an IV formulation as well to determine maximum exposure based on the IV data and a comparison with the oral formulation. A limited number of animal bioavailability studies have been reported using cocrystals. One study on the pharmaceutical cocrystal of a monophosphate salt with phosphoric acid mentions that excellent in vivo performance was observed, but no details about the study are given.(13b) A hemitartaric acid cocrystal of l-883555 was given orally to rhesus monkeys.(56) Four animals were used and a dose of 3 mg/kg (based on the parent compound) was administered. A methocel formulation was used, but it was not clear if a solution or suspension was produced. The cocrystal was found to be 15 times more bioavailable than the parent compound based on the maximum blood concentration (C max) values. A dog study compared a 1:1 carbamazepine/saccharin cocrystal with the marketed immediate release tablets of carbamazepine(54) (Tegretol containing carbamazepine form III). Four dogs were used and samples were taken up to 12 h post dose. The ground cocrystal (particle size <53 nm) was mixed with lactose in a dry blending step and placed into capsules containing a dose of 200 mg of carbamazepine. The pharmacokinetic parameters (AUC, C max, T max) were all found to be similar to the marketed product. This study noted that cocrystals can serve as a model for addressing physicochemical problems of a pharmaceutical compound (i.e., stability, solubility, dissolution), but will not overcome issues of metabolism or pharmacology. For dog studies of a 1:1 2-[4-(4-chloro-2-fluorphenoxy)phenyl]pyrimidine-4-carboxamide/glutaric acid cocrystal, a simple powder in capsule formulation was used at two dose levels (5 and 50 mg/kg).(48) The cocrystal was compared directly to the crystalline API (2-[4-(4-chloro-2-fluorphenoxy)phenyl]pyrimidine-4-carboxamide). Six dogs were used and samples were collected for 36 h post dose. The mean C max values for the 5 mg dose were 89 and 25 ng/mL for the cocrystal and parent compound, respectively. For the 50 mg dose, the C max values were 278 and 89 ng/mL for the cocrystal and parent compound, respectively. The cocrystal was found to be over three times more bioavailable than the parent material in these studies using only powder in a capsule as a formulation. It should be noted that the increase in dose was not proportional to the increase in exposure. Intrinsic dissolution experiments showed the cocrystal to be 18 times more soluble than the parent material in pure water and after 90 min the pellet showed very minor XRPD peaks due to the parent material. Exposure of the pellets to water for 24 h showed complete conversion to the parent material. Even though it is possible that the cocrystal may have dissociated in the animal studies, the increase in bioavailability and exposure was still significant. The 1:1 AMG 517/sorbic acid cocrystal(47) was compared to the parent free base in a rat bioavailability study using 10% (w/v) Pluronic F108 in OraPlus suspensions of free base (500 mg/kg) and cocrystal (10, 30, 100, 500 mg/kg). A significant increase in bioavailability was observed for the cocrystal. It was found that a 30 mg/kg dose of the cocrystal resulted in comparable exposure to a 500 mg/kg dose of the free base. This is another example where the cocrystal was found to dissociate in FaSIF, but displayed significantly higher solubility than the parent compound before it dissociated. This higher solubility may increase exposure if it stays in solution while it passes through the small intestine. Although the number of examples is limited, cocrystals can significantly increase the bioavailability of poorly soluble compounds. There is not always a direct in vitro/in vivo correlation and even examples of dissociated cocrystals in in vitro studies can provide improved performance in animal studies. III Additional Development Factors A Scale-up In order for pharmaceutical cocrystalline materials to move from small scale screening exercises to a viable option for development and ultimately drug products, scalable (kilo to multikilo) processes offering high cocrystal purity and yields must be devised and established. Cocrystal quantities of milligrams to a few grams are typically produced depending on the types of characterization and/or initial physicochemical studies (rate dissolution, solubility, bioavailability, etc.) the materials are subjected to. A recent survey of the open literature showed that slow evaporation and grinding are the two most common techniques for cocrystal growth; however, these approaches possess obvious limitations upon scale-up, and thus additional routes must be formulated.(69) In one account, the preparation of a carbamazepine/saccharin cocrystal was produced on a 30 g scale through solution crystallization.(54) Within this procedure, the components were dissolved in a mixture of ethanol and methanol (∼3:1) and refluxed at 70 °C for 1 h. The temperature was then lowered, and the precipitate was filtered, dried, and characterized as the 1:1 cocrystal of carbamazepine and saccharin. Interestingly, under the reaction conditions selected, seeding was not necessary to produce the desired cocrystalline form in high purity. Recently a detailed report on the scalable solution-crystallization process of a carbamazepine/nicotinamide cocrystal was described.(69) Outlined within the crystallization methodology are three criteria to be examined: (a) determine an appropriate solvent system; (b) identify the pathway, through multicomponent solid−liquid phase equilibrium diagrams, to produce the desired form; (c) determine a mechanism to induce nucleation and control the desaturation kinetics of the process. Through a seeding strategy in ethanol, the cocrystal was successfully produced on a 1 L scale with yields in excess of 90%. The construction and use of ternary phase diagrams should be considered when scaling up cocrystals from solution because information about the relationship between equilibria of the solid phases and solvent choices is obtainable. It is critical to determine and map the solubilities of the individual components since the phase region where the most thermodynamically stable cocrystal is located will be altered based on whether or not they possess similar solubilities in a given solvent. 14,70,71 As pharmaceutically based cocrystalline materials move further into development and become viable options as marketed products, scaleable cocrystal processes must be evaluated and optimized. B Cocrystal Polymorphism Searching for polymorphs of a particular compound is commonplace in solid-state pharmaceutics. Since polymorphic compounds can potentially possess drastically different physical and chemical properties, considerable efforts are taken to identify and characterize all forms during development. It is not surprising that polymorphic cocrystals can also exist(72) and possess varying physicochemical properties between forms. Detailed below are three examples of API-based polymorphic cocrystals and one example of an extensive polymorph screen on a cocrystalline material. A conformational polymorphic set of 1:1 cocrystals was observed when a chloroform solution of caffeine and glutaric acid were allowed to slowly evaporate.(73) The two different morphologies, rods (Form I) and blocks (Form II), crystallize concomitantly with identical molecular connectivities; however, differences arise in the torsional angles of the methylene carbons on the acid. Interestingly, each of the forms could be produced individually through mechanical grinding. In the absence of solvent or when a fairly nonpolar solvent was used, Form I was formed; however, when a more polar solvent was utilized, Form II resulted. Form II was found to be more stable with respect to humidity, as Form I displayed partial conversion to Form II after 1 day at 43% RH, with full conversion to Form II after 1 day at 75% RH.(49) This example clearly shows the differences in stability that polymorphic cocrystalline forms can possess. In another example, when an equimolar mixture of chlorzoxazone and 2,4-dihydroxybenzoic acid are evaporated from tetrahydrofuran (Form I) or ethyl acetate (Form II), 1:1 polymorphic cocrystals are generated.(74) Upon mechanical grinding of the individual components Form II was only produced, and solvent-assisted grinding or heating a sample of Form I results in full conversion to Form II. Piroxicam is known to exist in two tautomeric forms in the solid state, a nonionized tautomer and a zwitterionic tautomer. From a cocrystallization screen, two 1:1 polymorphic cocrystals were formed between piroxicam and 4-hydroxybenzoic acid.(6) Interestingly, the hydrogen bonding patterns are different between forms (this is arguably the first report of cocrystal synthon polymorphism),(75) as well as, in one form the piroxicam nonionized tautomer exists, while in the other the zwitterionic tautomer is observed. Unlike the previous two examples, in the case of the 1:1 cocrystal of carbamazepine and saccharin (Form I), an extensive polymorphic screen was conducted on one form.(54) By means of high-throughput crystallization, 480 experiments including saccharin and carbamazepine in various solvents and solvent mixtures were performed, yielding 156 solid materials which were characterized by XRPD or Raman spectroscopy. No polymorphic forms of the cocrystal were observed. Additionally, solvent-assisted mechanical grinding experiments were tried, using 24 different solvents. The remaining solids were characterized by XRPD, resulting, once again, in only the original cocrystal form. Finally, slurry conversion experiments utilizing seven different solvents at ambient temperatures for four days were attempted. The remaining solids were characterized by XRPD, displaying only the initial cocrystal form. Furthermore, dissociation of the cocrystal was not observed from the seven solvents, giving additional insight into the solution stability of the cocrystalline material. It should be noted, however, that a second polymorph of a 1:1 cocrystal of carbamazepine/saccharin (Form II) was found using a polymer heteronuclei crystallization media, and the hydrogen bonding patterns for the two forms are shown in Figure 9.(76) Polymorphism of cocrystals will attract more attention as cocrystals continue to gain momentum during the development of new pharmaceuticals. As with salts, cocrystal polymorphs offer additional options to alter properties, increase patent protection, and improve marketed formulations. C Intellectual Property (IP) and Lifecycle Management Patents have become a critical element of drug development, especially when covering solid forms. There have been limited reports on cocrystals and IP, 78,79 but more information on this area is expected as the field grows. Pharmaceutical patents can cover a number of different areas, including composition of matter (molecular structure, solid form, or formulation), method of use (medical indication), and manufacturing processes. In order for an invention to qualify for patent coverage, it must satisfy three criteria: novelty, utility, and nonobviousness. For solid form patent applications directed to pharmaceuticals in general, utility is not usually problematic, and the examples in this paper readily show examples of utility of new cocrystals above and beyond the therapeutic effect of the API. For a solid form to be novel, it cannot appear in the prior art either expressly or inherently. For most pharmaceutical cocrystals, prior art is limited since the coformer would likely not be published in connection with the crystallization of the API. This lack of prior art is an advantage from the IP perspective. The third area is being nonobvious, which may be viewed, in at least some circumstances, as correlating with predictability. Crystal engineering is certainly an advantage when trying to decide on possible coformers, but there is no guarantee that a cocrystal will form. Computational analyses are also not able to reliably predict the structure or properties of cocrystals at this point in time, which adds to the nonobvious nature of solid forms in general and especially cocrystals. Cocrystals represent a broad patent space since there is a large number of coformers available based on the possible compounds in the EAFUS (Everything Added to Food in the US) and GRAS (Generally Regarded as Safe) lists.(24) However, because of the lack of predictability in the field, it is expected that in many circumstances patent coverage will be narrow. Cocrystals can also play a role in lifecycle management.(78) Lifecycle management can involve drug product improvements along with new solid forms. Early in the development process, chemical structures are patented and additional IP protection can be obtained by patenting different solid forms throughout development. If an approved drug product contains a new patented solid form, especially where the solid form offers a commercial advantage over the original form, the solid form patent might provide meaningful IP protection after the expiration of the original patent. However, a solid form that was not found by the innovator, but was found and patented by a competitor, could significantly alter this strategy. Cocrystal screens for potential blockbuster drugs could end up being very large in order to protect, not only the cocrystals found, but also any polymorphs, hydrates, solvates, or other solid forms of the individual cocrystals. From a regulatory point of view for generic products, cocrystals may present an interesting option. Currently, when generic pharmaceutical companies use polymorphs and hydrates as alternatives to ethical drugs, they file Abbreviated New Drug Applications (ANDAs), which requires the submission of minimal bioavailability and clinical data and does not require proving safety or efficacy. New salts of an API, however, use a slightly different regulatory pathway, a so-called 505(b)(2) application, and require more testing and clinical data than an ANDA submission. The classification of cocrystals as a generic has not yet been addressed.(78) Cocrystals contain nonionic interactions like hydrates, but they also contain substances with possible toxicity issues, similar to salts. The decision on how to regulate cocrystals for generic products may affect their use in the generic industry. Cocrystals will raise IP and regulatory questions as more of these compounds are developed, moved later into development, and eventually marketed. As with any solid form, they will offer their own challenges and many issues will need to be dealt with on a case by case basis. IV Conclusions One can clearly see a place for cocrystals within the pharmaceutical market. On the basis of the limited examples available, some general comments can be made on the physicochemical properties of cocrystals. Melting points are altered for most cocrystals, with approximately 51% resulting in melting points between those of the API and coformer and 39% resulting in lower melting points. Correlations with other parameters, such as solubility, are limited and will be complex due to the multicomponent nature of the cocrystals. In many cases, improved stability, such as resistance to hydrate formation, has been shown for cocrystals. However, general trends are not evident and each system needs to be evaluated to determine if improvements are obtained. Improved solubility for poorly soluble compounds has been achieved using cocrystals. Limited studies suggest that salts will provide a larger increase in solubility if they are available. For poorly soluble neutral compounds, cocrystals are a very feasible approach to improving solubility. Cocrystals can provide higher and lower dissolution rates compared to the API. Dissociation is an important consideration in analyzing data from these experiments. It was shown that significant increases in bioavailability are possible with cocrystals, even when dissociation of the cocrystal is suspected based on in vitro studies. Other aspects of development, such as polymorphism and scale-up, will need to be examined for cocrystals. Processes to produce cocrystals on a large scale will likely require different approaches, such as those based on ternary solubility phase diagrams. Cocrystals will provide additional options for IP, regulatory, and lifecycle management for new and old drugs and will provide additional challenges as they continue through the development process. To date, no cocrystalline drug products appear to be on the market, although there is no doubt that cocrystals are present in pharmaceutical drug pipelines and it is only a matter of time before this imagination becomes a reality.
Author and article information
Journal
Journal ID (nlm-ta): Chem Sci
Journal ID (iso-abbrev): Chem Sci
Journal ID (publisher-id): SC
Journal ID (coden): CSHCBM
Title:
Chemical Science
Publisher:
The Royal Society of Chemistry
ISSN
(Print):
2041-6520
ISSN
(Electronic):
2041-6539
Publication date
(Electronic, pub):
10
October
2022
Publication date
(Electronic, collection):
26
October
2022
Publication date PMC-release: 10
October
2022
Volume: 13
Issue: 41
Pages: 12100-12106
Affiliations
[a]
Research Department, Chemistry Division, United States Navy – Naval Air Systems Command
(NAVAIR), Naval Air Warfare Center, Weapons Division (NAWCWD)
1900 N. Knox Road, China Lake
California
93555
USA
[b]
Department of Chemistry, University of Michigan
930 North University Avenue
Ann Arbor
Michigan 48109-1055
USA
matzger@
123456umich.edu
Author information
Adam J. Matzger
https://orcid.org/0000-0002-4926-2752
Article
Publisher ID: d2sc03015bDOI: 10.1039/d2sc03015b
PMC ID: 9600225
SO-VID: 94706f76-0a47-41bc-87ca-3bc308a584e6
Copyright © This journal is © The Royal Society of Chemistry
History
Date
received
: 30
May
2022
Date
accepted
: 29
September
2022
Page count
Pages: 7
Funding
Funded by:
Office of Naval Research, doi 10.13039/100000006;
Award ID: N00014-19-1-2086
Award ID: N00014-22-1-2101
Categories
Subject:
Chemistry
Custom metadata
pubstatus Paginated Article
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