The use of polymer heteronuclei for crystalline polymorph selection

A method for the production of crystalline polymorphs from solution is described which utilizes a diverse set of polymer heteronuclei. Application to crystalline polymorph selection for the important pharmaceuticals acetaminophen and carbamazepine is demonstrated. This method provides a new paradigm for polymorph selection, where solvent and temperature conditions can be chosen on the basis of process considerations and the polymer heteronucleus can be varied for specific polymorph production.     

How many more polymorphs of ROY remain undiscovered

With 12 crystal forms, 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecabonitrile (a.k.a. ROY) holds the current record for the largest number of fully characterized organic crystal polymorphs. Four of these polymorph structures have been reported since 2019, raising the question of how many more ROY polymorphs await future discovery. Employing crystal structure prediction and accurate energy rankings derived from conformational energy-corrected density functional theory, this study presents the first crystal energy landscape for ROY that agrees well with experiment. The lattice energies suggest that the seven most stable ROY polymorphs (and nine of the twelve lowest-energy forms) on the Z′ = 1 landscape have already been discovered experimentally. Discovering any new polymorphs at ambient pressure will likely require specialized crystallization techniques capable of trapping metastable forms. At pressures above 10 GPa, however, a new crystal form is predicted to become enthalpically more stable than all known polymorphs, suggesting that further high-pressure experiments on ROY may be warranted. This work highlights the value of high-accuracy crystal structure prediction for solid-form screening and demonstrates how pragmatic conformational energy corrections can overcome the limitations of conventional density functionals for conformational polymorphs.

Crystal structure prediction suggests that the low-energy polymorphs of ROY have already been found, but a new high-pressure form is predicted.     

Polymorph selectivity under nanoscopic confinement

Polymorph selectivity has been achieved during crystallization of anthranilic acid (AA) and 5-methyl-2-[(2-nitrophyenyl)amino]-3-thiophenecarbonitrile (ROY), both considered benchmarks of polymorphic behavior, within nanoporous glass beads and polymer monoliths. Whereas polymorph III of AA crystallizes from the melt on nonporous glass beads or within larger pores, the metastable polymorph II crystallizes in pores with diameters <23 nm, with the selectivity toward this form increasing with decreasing pore size. Of the six ROY polymorphs characterized by single-crystal X-ray diffraction, the yellow form (Y) crystallizes during evaporation of pyridine solutions imbibed by the 30-nm cylindrical pores of porous polycyclohexylethylene (p-PCHE) monoliths. Although both R and ON grow from the melt on the external surfaces of PCHE, only the red form (R) crystallizes in the pores. Amorphous ROY also forms in p-PCHE pores during evaporation from pyridine solutions, subsequently crystallizing to the R nanocrystals upon heating. Although heterogeneous nucleation on the pore walls may play a role, these observations suggest that nucleation and polymorph selectivity is governed by critical size constraints imposed by the ultrasmall pores. The ability to achieve polymorph selectivity in both glass and polymer matrices suggests wide-ranging compatibility with various organic crystalline solids, promising a new approach to controlling polymorphism and searching for unknown polymorphs.     

New polymorphs of ROY and new record for coexisting polymorphs of solved structures

With six polymorphs coexisting at room temperature, 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY) is the top system in the current Cambridge Structural Database (Feb. 2005) for the number of polymorphs of solved crystal structures. Here we report two new ROY polymorphs, Y04 and YT04, and the crystal structure of YT04. Y04 is a metastable polymorph that tends to crystallize first from a melt at room temperature, and YT04 is a product of solid-state transformation of Y04. Despite its late discovery, YT04 is the densest among the polymorphs at 25 degrees C and likely the second most stable at 0 K. The conformation of ROY in YT04 is similar to those in the other two yellow polymorphs (Y and YN) but significantly different from those in the orange and red colored polymorphs (ON, OP, ORP, and R). Having escaped years of solution crystallization in several laboratories, Y04 and YT04 exemplify polymorphs that are likely missed by solvent-based screening and discovered through alternative routes.     

Cross-nucleation between ROY polymorphs

Cross-nucleation between polymorphs is a newly discovered phenomenon important for understanding and controlling crystal polymorphism. It contradicts Ostwald's law of stages and other theories of crystallization in polymorphic systems. We studied the phenomenon in the spontaneous and seeded melt crystallization of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (ROY), currently the most polymorphic system of known structures. We observed extensive and sometimes selective cross-nucleation between ROY polymorphs. Certain polymorphs could not nucleate without the aid of others. The new polymorph was found to be more or less thermodynamically stable than the initial one but to always grow faster than or as fast as the initial one. The temperature and surface characteristics of the seed crystals affected the occurrence of cross-nucleation. Our results show that the pathway of crystallization in polymorphic systems is not determined solely by the initial nucleation, but also by cross-nucleation between polymorphs and the different growth rates of polymorphs. This study identified a new metastable polymorph of ROY, the 10th of the family.     

Rapid liquid chromatography-tandem mass spectrometry method for the determination of a broad mixture of pharmaceuticals in surface water

Herein, a new method for the detection of 13 different pharmaceuticals and one metabolite in surface water at low ng/L levels is described. The method utilizes ultra performance liquid chromatography-tandem mass spectrometry and a solid-phase extraction sample preparation. Mean method detection limits were low (4.10 ng/L) and overall solid-phase extraction recovery and reproducibility was adequate (mean recovery, 77.9%; mean RSD, 7.3%). The method allows for quick run times and minimal solvent use as compared with other previously reported high performance liquid chromatography-based methods. Application of this method for the detection of pharmaceuticals in Tennessee River surface water determined that caffeine, sulfamethoxazole, and carbamazepine were frequently detected (100% of samples). Trimethoprim was moderately detected (30% of samples); acetaminophen, atorvastatin, and lovastatin were infrequently detected (10% of samples); and ciprofloxacin, diltiazem, fluoxetine, levofloxacin, norfluoxetine, ranitidine, and sertraline were not detected. This study reports the first detection of lovastatin in surface water.     

Hydrogen bonding interactions between adsorbed polymer molecules and crystal surface of acetaminophen

The objective of this work was to investigate whether or not the hydrogen bonding interaction between polymer and crystal surface can be detected by the etching pattern changes in the presence of polymers. The (010) face of acetaminophen single crystal was used as a model solid surface. The etching patterns on the (010) face of acetaminophen crystal by water are in the directions of a- and c-axes, which are the same as the directions of the dominant attachment energies on the (010) face. In the presence of polymer, the hydrogen bonding interactions between adsorbed polymer and crystal surface can affect surface diffusion of acetaminophen molecules and change the etching patterns in the direction of a-axis, i.e., the direction of one hydrogen bond chain. Studies with 2-hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) and poly(vinyl alcohol) (PVA) showed that polymers, which can form hydrogen bonds with acetaminophen crystal surface, can change etching patterns in the direction of a-axis. Study with Dextran suggested that if a polymer cannot form hydrogen bonds with crystal surface due to steric repulsion, it will not change the etching pattern in the direction of a-axis. Studies with poly(ethylene glycol) (PEG) and poly(propylene glycol) (PPG) further confirmed that only if a polymer can form hydrogen bonds with acetaminophen on crystal surface, the etching patterns in the direction of a-axis will be affected. The study results suggest that in the presence of polymers, the etching pattern change in the direction of hydrogen bond chain, the a-axis of acetaminophen crystals, can be used to indicate the existence of the hydrogen bonding interactions between adsorbed polymers and acetaminophen crystal surface.     

Structural diversity in two-dimensional coordination polymers constructed from simple building-blocks; a rare example of coordination polymer polymorphs structurally characterised from multiple crystals

A family of two-dimensional coordination polymers formed from the reaction of Cd(NO(3))(2) with pyrazine or pyrimidine is reported, including rare examples of polymorphic coordination polymers which crystallise as multiple crystals. Six coordination polymers have been structurally characterised, four for pyrazine and two for pyrimidine-based systems, all of which form two-dimensional arrays utilising pyrazine/pyrimidine bridging, in some instances in combination with nitrate bridging. The compounds form either 4(4) grids (1,3,4,5), or in one instance, a 6(3) herringbone sheet structure (2). In the case of 3, two polymorphs have been identified, 3a and 3b, in which the three-dimensional arrangements of the coordination polymers differ only in the relative ordering of adjacent two-dimensional sheets. It was found that these two polymorphs crystallise in a simultaneous fashion such that each crystal studied was found to contain regions of both polymorphs and was believed to be a multiple crystal. Assessment of the phase purity of the product from the reaction of Cd(NO(3))(2) with either pyrazine or pyrimidine indicates that compounds 1and 5 are not formed when the products are formed by rapid precipitation but only when using slow-diffusion methods. It is also apparent that in almost all instances more than one product is formed from a given reaction thereby illustrating the complexity of coordination polymer formation even when using simple building-blocks. For the crystal engineer this complexity is perhaps best illustrated by the simultaneous formation of 3a and 3b where no chemical interactions differentiate the two polymorphs, presenting a seemingly insurmountable complexity in the engineering of these systems.     

The prediction, morphology, and mechanical properties of the polymorphs of paracetamol.

The analgesic drug paracetamol (acetaminophen) has two reported metastable polymorphs, one with better tableting properties than the stable form, and another which remains uncharacterized. We have therefore performed a systematic crystal structure prediction search for minima in the lattice energy of crystalline paracetamol. The stable monoclinic form is found as the global lattice-energy minimum, but there are at least a dozen energetically feasible structures found, including the well-characterized metastable orthorhombic phase. Hence, we require additional criteria to reduce the number of hypothetical crystal structures that can be considered as potential polymorphs. For this purpose the elastic properties and vapor growth morphology of the known and predicted structures have been estimated using second-derivative analysis and the attachment-energy model. These inexpensive calculations give reasonable agreement with the available experimental data for the known polymorphs. Some of the hypothetical structures are predicted to have a low growth rate and plate-like morphology, and so are unlikely to be observed. Another is only marginally mechanically stable. Thus, this first consideration of such properties in a crystal-structure prediction study appears to reduce the number of predicted polymorphs while leaving a few candidates for the uncharacterized form.     

Polymorphism in crystalline cinchomeronic acid

The structural relationship between the two crystal forms of cinchomeronic acid (CA 3,4-dicarboxypyridine) has been investigated by single crystal X-ray diffraction, IR and Raman spectroscopy and solid state NMR spectroscopy, showing that the two polymorphs form a monotropic system, with the orthorhombic form I being the thermodynamically stable form, while the monoclinic form II is unstable. In both forms CA crystallizes as a zwitterion and decomposes before melting. The crystal structure and spectroscopic analysis indicate that the difference in stability can be ascribed to the strength of the hydrogen-bonding patterns established by the protonated N-atom and the carboxylic/carboxylate O-atoms.     

Understanding the influence of polymorphism on phonon spectra: lattice dynamics calculations and terahertz spectroscopy of carbamazepine

Rigid molecule atomistic lattice dynamics calculations have been performed to predict the phonon spectra of the four polymorphs of carbamazepine, and these calculations predict that there should be differences in the spectra of all four forms. Terahertz spectra have been measured for forms I and III, and there are clearly different features between polymorphs' spectra, that are accentuated at low temperature. While carbamazepine adopts the same hydrogen bonded dimers in all of its known polymorphs, the calculations show that differences in packing arrangements of the dimers lead to changes in the frequency ranges for each type of hydrogen bond vibration, giving a physical explanation to the observed differences between the spectra. Although the agreement between calculated and observed spectra does not allow a definitive characterization of the spectra, it is possible to make tentative assignments of many of the observed features in the terahertz region for the simpler form III; we can only make some tentative assignments of specific modes in the more complex spectrum of form I. While harmonic rigid molecule lattice dynamics shows promise for understanding the differences in spectra between polymorphs of organic molecules, discrepancies between observed and calculated spectra suggest areas of improvement in the computational methods for more accurate modeling of the dynamics in molecular organic crystals.     

Thermal studies of isoniazid and mixtures with rifampicin

Rifampicin–Isoniazid mixture is a frequently used product in the treatment of tuberculosis. Rifampicin exhibits polymorphism and exists in two polymorphic forms: the stable form I and the metastable form II. The aim of this work was to evaluate the thermal behavior of the binary mixtures of polymorphs I and II of rifampicin and isoniazid by using DSC. Mixtures of different forms (rifampicin form I and II) showed interaction with isoniazid indicating that the mixtures are less stable compared to the drug alone. Interaction was observed in case of both polymorphs of rifampicin.     

A new ionic liquid surface‐imprinted polymer for selective solid‐phase‐extraction and determination of sulfonamides in environmental samples

Toward improving the selective adsorption performance of molecularly imprinted polymers in strong polar solvents, in this work, a new ionic liquid functional monomer, 1‐butyl‐3‐vinylimidazolium bromide, was used to synthesize sulfamethoxazole imprinted polymer in methanol. The resulting molecularly imprinted polymer was characterized by Fourier transform infrared spectra and scanning electron microscopy, and the rebinding mechanism of the molecularly imprinted polymer for sulfonamides was studied. A static equilibrium experiment revealed that the as‐obtained molecularly imprinted polymer had higher molecular recognition for sulfonamides (e.g., sulfamethoxazole, sulfamonomethoxine, and sulfadiazine) in methanol; however, its adsorption of interferent (e.g., diphenylamine, metronidazole, 2,4‐dichlorophenol, and m‐dihydroxybenzene) was quite low. ¹H NMR spectroscopy indicated that the excellent recognition performance of the imprinted polymer was based primarily on hydrogen bond, electrostatic and π‐π interactions. Furthermore, the molecularly imprinted polymer can be employed as a solid phase extraction sorbent to effectively extract sulfamethoxazole from a mixed solution. Combined with high‐performance liquid chromatography analysis, a valid molecularly imprinted polymer‐solid phase extraction protocol was established for extraction and detection of trace sulfamethoxazole in spiked soil and sediment samples, and with a recovery that ranged from 93–107%, and a relative standard deviation of lower than 9.7%.     

Synthesis and application of hypercrosslinked polymers with weak cation-exchange character for the selective extraction of basic pharmaceuticals from complex environmental water samples

The synthesis of high specific surface area sorbents (HXLPP-WCX) in the form of hypercrosslinked polymer microspheres with narrow particle size distributions, average particle diameters around 6 μm, and weak cation-exchange (WCX) character, is described. The WCX character arises from carboxylic acid moieties in the polymers, derived from the comonomer methacrylic acid. A novel HXLPP-WCX sorbent with an attractive set of chemical and physical properties was then used in an off-line solid-phase extraction (SPE) protocol for the selective extraction of a group of basic compounds from complex environmental samples, a priority being the clean separation of the basic compounds of interest from acidic compounds and interferences. The separation power of the new sorbent for basic pharmaceuticals was compared to two commercially available, mixed-mode sorbents, namely Oasis WCX and Strata-X-CW. Under identical experimental conditions, HXLPP-WCX was found to deliver both higher capacity and better selectivity in SPE than either of the two commercially available materials. In an optimised SPE protocol, the HXLPP-WCX sorbent gave rise to quantitative and selective extractions of low μg l⁻¹ levels of basic pharmaceuticals present in 500 ml of river water and 250 ml of effluent waste water.     

Transformation of metastable forms of acetaminophen studied by thermal Fourier transform infrared (FT-IR) microspectroscopy

A novel Fourier transform infrared (FT-IR) microspectroscopy equipped with a micro hot stage (thermal FT-IR microscopic system) was used to quickly study the phase transformation of acetaminophen polymorphs by a one-step process. Acetaminophen was sealed in KBr disc on the first and second heating processes under this system. The results indicate that the contour IR profile of form I acetaminophen in the first heating process changed dramatically only near 165 degrees C, but in the re-heating process exhibited a considerable alteration in peak intensity, band width and position near the temperatures at 85, 118 and 153 degrees C. A glassy form of acetaminophen was obtained after rapidly cooling the melted acetaminophen from 200 to 25 degrees C. The glassy acetaminophen was recrystallized at 85 degrees C to transform to the form III of acetaminophen in the reheating process, and then transformed to its form II near 118 degrees C. The thermal FT-IR microscopic system is a simple, quick and timesaving tool for investigation of the thermo-dependent molecular structure of acetaminophen polymorphs in the processes of recrystallization and polymorphic transition.     

Conformational dimorphism in o‐nitrobenzoic acid: alternative ways to avoid the O…O clash

Polymorphism is a challenging phenomenon and the competitive packing alternatives which are characteristic for polymorphs may be encountered for essentially rigid molecules. A second crystal form of the well known compound o‐nitrobenzoic acid, C₇H₅NO₄, an important intermediate in the production of dyes, pharmaceuticals and agrochemicals, is described. Although obtained serendipitously, its intra‐ and intermolecular features match expectations from database searches and theoretical calculations. O—H…O hydrogen‐bonded carboxylic acid dimers represent the building blocks in both polymorphs. For steric reasons and in agreement with a calculated potential energy surface, the carboxylic acid and nitro groups cannot simultaneously be coplanar with the benzene ring but have to tilt. In the well established crystal form, this out‐of‐plane torsion is more pronounced for the nitro substituent. In contrast, the new polymorph is characterized by a major tilt of the carboxylic acid group. The molecules in both alternative crystal forms achieve a similar compromise with respect to acceptable intramolecular O…O contacts.     

Simultaneous determination of various pharmaceutical compounds in water by solid-phase extraction-liquid chromatography-tandem mass spectrometry

A solid-phase extraction (SPE) followed by liquid chromatography-electrospray ionisation tandem mass spectrometry (LC-ESI-MS-MS) method was developed and validated for simultaneous analysis of 11 pharmaceutical residues (propranolol, sulfamethoxazole, meberverine, thioridazine, carbamazepine, tamoxifen, mecoprop, indomethacine, diclofenac, meclofenamic acid and monensin) in environmental water samples. The collision energy chosen for the multiple reaction monitoring (MRM) experiment was optimised. A number of parameters that may affect the recovery of the pharmaceuticals, such as the type of SPE cartridges, eluents, as well as water properties including pH value, salinity and concentration of colloid and surfactant were investigated. It is shown that the Oasis HLB SPE cartridge produced the best recoveries of the target pharmaceuticals while methanol was efficient in eluting pharmaceuticals from SPE cartridges. The recovery of some target compounds was enhanced with increasing salinity, but reduced by increasing pH value, and unaffected by surfactant concentration (0-10 microg/l). The recovery of most compounds was slightly increased by the presence of colloids (0-10 mg/l), which however caused a reduction in recovery for sulfamethoxazole and meberverine. The optimised method was further verified by performing spiking experiments in river water and seawater matrices, with good recovery and reproducibility for all except two compounds. The established method was successfully applied to environmental water samples from East Sussex, UK, for the determination of the target pharmaceuticals.     

Thermal Analysis,Microcalorimetry and Combined Techniques for the Study of Pharmaceuticals

Modern thermal analysis, microcalorimetry and new emerging combined techniques which deliver calorimetric, microscopic and spectroscopic data offer a powerful analytical battery for the study of pharmaceuticals. These techniques are very useful in all steps of development of new drug products as well as methods for quality control in production. The characterization of raw materials enables to understand the relationships between polymorphs, solvates and hydrates and to choose the proper development of new drug products with very small amount of material in a very short time. Information on stability, purity is valuable for new entities as well as for marketed drug substances from different suppliers. Excipients which vary from single organic or inorganic entity to complexes matrixes or polymers need to be characterized and properly controlled. The thermodynamic phase-diagrams are the basis of the studies of drug-excipients interactions. They are very useful for the development of new delivery systems. A great number of new formulations need proper knowledge of the behaviour of the glass transition temperature of the components. Semi-liquid systems, interactions in aqueous media are also successfully studied by these techniques. This revised version was published online in August 2006 with corrections to the Cover Date.     

Polymorphic and pseudomorphic transformation behavior of acyclovir based on thermodynamics and crystallography

Acyclovir (ACV) has two polymorphs, anhydrate 1 and anhydrate 2, and two hydrates, 2/3 hydrate and dihydrate. The effect of polymorphic transformation of ACV on the temperature and humidity was evaluated by simultaneous XRD-DSC and vapor sorption analysis. Each crystal structure of ACV was analyzed by single crystal analysis and powder X-ray diffraction analysis. On the polymorphic and pseudomorphic transformation, anhydrate 1 did not directly transform to anhydrate 2, but transform through 2/3 hydrate and dihydrate due to relative humidity and temperature. According to the molecular packing for four crystals, there are two packing manners for purine moiety. Anhydrate 1, anhydrate 2, 2/3 hydrate and dihydrate were packed in parallel, anti parallel, mixture of parallel–anti parallel and parallel manners, respectively. Base on the packing manner of ACV, it can be seen why the phase transformation occurs with readily or with difficulty. The thermodynamic relation of anhydrate form 1 and form 2 was evaluated by DSC and microcalorimetry. It was found that these two forms are monotropic forms, with anhydrate form I is stable form and it transform to a new form 3 at 443.2 K.     

Structural landscape investigations on bendable plastic crystals of isonicotinamide polymorphs

Three polymorphs (forms I, II and V) of isonicotinamide (INA) were mechanically flexible and exhibited one-dimensional (1D) plasticity. Anisotropic intermolecular interactions contribute to the plasticity of single crystals: weak dispersive interactions between slip planes such as 1D columns in forms I and II or 2D layers in form V were stabilized by strong hydrogen bonds, allowing the layer or column's surface to glide smoothly without hindrance. The disparity of intermolecular interactions on plastic properties of INA polymorphic crystals was confirmed by energy framework analysis, nanoindentation tests and micro-Raman spectroscopy. The crystal which exhibits plastic property provides a promising application in pharmaceuticals and material sciences.