Crystal size, shape, and conformational changes drive both the disappearance and reappearance of ritonavir polymorphs in the mill.

Organic compounds can crystallize in different forms known as polymorphs. Discovery and control of polymorphism is crucial to the pharmaceutical industry since different polymorphs can have significantly different physical properties which impacts their utilization in drug delivery. Certain polymorphs have been reported to 'disappear' from the physical world, irreversibly converting to new ones. These unwanted polymorph conversions, initially prevented by slow nucleation kinetics, are eventually observed driven by significant gains in thermodynamic stabilities. The most infamous of these cases is that of the HIV drug ritonavir (RVR): Once its reluctant form was unwillingly nucleated for the first time, its desired form could no longer be produced with the same manufacturing process. Here we show that RVR's extraordinary disappearing polymorph as well as its reluctant form can be consistently produced by ball-milling under different environmental conditions. We demonstrate that the significant difference in stability between its polymorphs can be changed and reversed in the mill-a process we show is driven by crystal size as well as crystal shape and conformational effects. We also show that those effects can be controlled through careful design of milling conditions since they dictate the kinetics of crystal breakage, dissolution, and growth processes that eventually lead to steady-state crystal sizes and shapes in the mill. This work highlights the huge potential of mechanochemistry in polymorph discovery of forms initially difficult to nucleate, recovery of disappearing polymorphs, and polymorph control of complex flexible drug compounds such as RVR.

Polymorphic Solid Solutions in Molecular Crystals: Tips, Tricks, and Switches.

Crystal polymorphism has been a topic of much interest for the past 20 years or so, especially since its scientific (and legal) importance to the pharmaceutical industry was realized. By contrast, the formation of solid solutions in molecular crystals has been overlooked despite its long-standing prevalence in the analogous field of inorganic crystals. Wilfully forgotten, crystalline molecular solid solutions may be very common in our world since molecular compounds are rarely produced with 100% purity, and impurities able to form solid solutions are difficult to reject via recrystallization. Given the importance of both polymorphism and solid solutions in molecular crystals, we share here some tips, tricks, and observations to aid in their understanding. First, we propose a nomenclature system fit for the description of molecular crystalline solid solutions capable of polymorphism (tips). Second, we highlight the challenges associated with their experimental and computational characterization (tricks). Third, we show that our recently reported observation that polymorph stabilities can change by virtue of solid solution formation is a general phenomenon, reporting it on a second system (switches). Our work focuses on the historically important compound benzamide forming solid solutions with nicotinamide and 3-fluorobenzamide.

Using Prenucleation Aggregation of Caffeine-Benzoic Acid as a Rapid Indication of Co-crystallization from Solutions.

Co-crystal design is a convenient way to remedy the poor biopharmaceutical properties of drugs. Most studies focus on experimental co-crystal screening or computational prediction, but hardly any work has been done toward fast, efficient, and reliable prediction of solution crystallization for co-crystal formation. Here, we study the caffeine-benzoic acid co-crystal system, due to its reported difficulty to crystallize from the solution phase. With this work, we investigate whether there is a link between prenucleation aggregation in solution and co-crystal formation and how to harness this for crystallization prediction. 1H and 13C NMR spectroscopy is used to study the prenucleation interaction between caffeine and benzoic acid in methanol, acetone, and acetonitrile as examples of common solvents. In this system, crystallization from methanol leads to no co-crystallization, from acetone to concomitant crystallization of co-crystal and caffeine, and from acetonitrile to pure co-crystal formation from solution. Strong heteromeric dimers were found to exist in all three solvents. Ternary phase diagrams were defined and a solution-accessible co-crystal region was found for all solvents. For this system, the prenucleation clusters found in solution could be linked to the crystallization of the co-crystal. Crystallization from DMSO did not yield the co-crystal and there were no detectable prenucleation aggregates. NMR spectroscopy to probe dimers in solution can thus be used as a fast, reliable, and promising tool to predict co-crystallization from specific solvents and to screen for suitable solvents for manufacturing and scale-up.

The role of solvation in proton transfer reactions: implications for predicting salt/co-crystal formation using the ΔpKa rule.

The ΔpKa rule is commonly applied by chemists and crystal engineers as a guideline for the rational design of molecular salts and co-crystals. For multi-component crystals containing acid and base constituents, empirical evidence has shown that ΔpKa > 4 almost always leads to salts, ΔpKa < -1 almost always leads to co-crystals and ΔpKa between -1 and 4 can be either. This paper reviews the theoretical background of the ΔpKa rule and highlights the crucial role of solvation in determining the outcome of the potential proton transfer from acid to base. New data on the frequency of the occurrence of co-crystals and salts in multi-component crystal structures containing acid and base constituents show that the relationship between ΔpKa and the frequency of salt/co-crystal formation is influenced by the composition of the crystal. For unsolvated co-crystals/salts, containing only the principal acid and base components, the point of 50% probability for salt/co-crystal formation occurs at ΔpKa ≈ 1.4, while for hydrates of co-crystals and salts, this point is shifted to ΔpKa ≈ -0.5. For acid-base crystals with the possibility for two proton transfers, the overall frequency of occurrence of any salt (monovalent or divalent) versus a co-crystal is comparable to that of the whole data set, but the point of 50% probability for observing a monovalent salt vs. a divalent salt lies at ΔpKa,II ≈ -4.5. Hence, where two proton transfers are possible, the balance is between co-crystals and divalent salts, with monovalent salts being far less common. Finally, the overall role played by the "crystal" solvation is illustrated by the fact that acid-base complexes in the intermediate region of ΔpKa tip towards salt formation if ancillary hydrogen bonds can exist. Thus, the solvation strength of the lattice plays a key role in the stabilisation of the ions.

The interplay of intra- and intermolecular errors in modeling conformational polymorphs.

Conformational polymorphs of organic molecular crystals represent a challenging test for quantum chemistry because they require careful balancing of the intra- and intermolecular interactions. This study examines 54 molecular conformations from 20 sets of conformational polymorphs, along with the relative lattice energies and 173 dimer interactions taken from six of the polymorph sets. These systems are studied with a variety of van der Waals-inclusive density functionals theory models; dispersion-corrected spin-component-scaled second-order Møller-Plesset perturbation theory (SCS-MP2D); and domain local pair natural orbital coupled cluster singles, doubles, and perturbative triples [DLPNO-CCSD(T)]. We investigate how delocalization error in conventional density functionals impacts monomer conformational energies, systematic errors in the intermolecular interactions, and the nature of error cancellation that occurs in the overall crystal. The density functionals B86bPBE-XDM, PBE-D4, PBE-MBD, PBE0-D4, and PBE0-MBD are found to exhibit sizable one-body and two-body errors vs DLPNO-CCSD(T) benchmarks, and the level of success in predicting the relative polymorph energies relies heavily on error cancellation between different types of intermolecular interactions or between intra- and intermolecular interactions. The SCS-MP2D and, to a lesser extent, ωB97M-V models exhibit smaller errors and rely less on error cancellation. Implications for crystal structure prediction of flexible compounds are discussed. Finally, the one-body and two-body DLPNO-CCSD(T) energies taken from these conformational polymorphs establish the CP1b and CP2b benchmark datasets that could be useful for testing quantum chemistry models in challenging real-world systems with complex interplay between intra- and intermolecular interactions, a number of which are significantly impacted by delocalization error.

Concerning Elusive Crystal Forms: The Case of Paracetamol.

Increasing commercial application of state of the art crystal structure prediction to aid solid form discovery of new molecular entities allows the experimentalist to target the polymorphs with desired properties. Here we remind ourselves that in this field the gap between such prediction and experimentation can be vast, the latter depending strongly on kinetic processes not accounted for in the computations. Nowhere is this gap more evident than in examples of so-called "elusive" polymorphs, forms that have been found difficult to crystallize, sometimes taking years to appear or sometimes disappearing altogether. In attempting to probe the origins of such phenomena this work targets a well-known, relatively simple molecule, paracetamol (PCM), and explores the structural and kinetic origins of its elusive nature. It is noted that in general comparisons of the kinetic factors (nucleation and crystal growth) between polymorphs have rarely been reported and of course in cases where one or more forms is "elusive" this will, by definition, be essentially impossible. PCM however offers a unique opportunity and we show how the recent discovery of the impact of metacetamol (MCM) in stabilizing PCM form II can be used to advantage, enabling otherwise impossible comparative kinetic experiments to be made. Resulting from this study we now appreciate that MCM has a selective impact in blocking the growth of the thickness and width of PCM form I while it has no impact on form II. This is interpreted in terms of strong adsorption of MCM on the {011} faces (width and thickness) of form I in orientations that inhibit crystal growth ("wrong" orientations). Of more significance here is the use of the additive in allowing an otherwise impossible comparison of linear growth rates of forms I and II. This leads to the appreciation that only through calculation of growth volumes can we finally appreciate how the relative growth kinetics lead inevitably to the elusive nature of Form II.

Transforming Computed Energy Landscapes into Experimental Realities: The Role of Structural Rugosity.

We exploit the possible link between structural surface roughness and difficulty of crystallisation. Polymorphs with smooth surfaces may nucleate and crystallise more readily than polymorphs with rough surfaces. The concept is applied to crystal structure prediction landscapes and reveals a promising complementary way of ranking putative crystal structures.

The Curious Case of 2-Propyl-1H-benzimidazole in the Solid State: An Experimental and Theoretical Study.

2-Propyl-1H-benzimidazole (2PrBzIm) is a small molecule, commercially available, which displays a curious behavior in the solid state. 2PrBzIm, although devoid of chirality by fast rotation about a single bond of the propyl group in solution, crystallizes as a conglomerate showing chiroptical properties. An exhaustive analysis of its crystal structure and a wide range of experiments monitored by vibrational circular dichroism spectroscopy eliminated all possibilities of an artifact. What remains is a new example of the unexplained phenomenon of persistent supramolecular chirality.

Facts and fictions about polymorphism.

We present new facts about polymorphism based on (i) crystallographic data from the Cambridge Structural Database (CSD, a database built over 50 years of community effort), (ii) 229 solid form screens conducted at Hoffmann-La Roche and Eli Lilly and Company over the course of 8+ and 15+ years respectively and (iii) a dataset of 446 polymorphic crystals with energies and properties computed with modern DFT-d methods. We found that molecular flexibility or size has no correlation with the ability of a compound to be polymorphic. Chiral molecules, however, were found to be less prone to polymorphism than their achiral counterparts and compounds able to hydrogen bond exhibit only a slightly higher propensity to polymorphism than those which do not. Whilst the energy difference between polymorphs is usually less than 1 kcal mol(-1), conformational polymorphs are capable of differing by larger values (up to 2.5 kcal mol(-1) in our dataset). As overall statistics, we found that one in three compounds in the CSD are polymorphic whilst at least one in two compounds from the Roche and Lilly set display polymorphism with a higher estimate of up to three in four when compounds are screened intensively. Whilst the statistics provide some guidance of expectations, each compound constitutes a new challenge and prediction and realization of targeted polymorphism still remains a holy grail of materials sciences.

Do metastable polymorphs always grow faster? Measuring and comparing growth kinetics of three polymorphs of tolfenamic acid.

The phenomenon of molecular crystal polymorphism is of central importance for all those industries that rely on crystallisation for the manufacturing of their products. Computational methods for the evaluation of thermodynamic properties of polymorphs have become incredibly accurate and a priori prediction of crystal structures is becoming routine. The computational study and prediction of the kinetics of crystallisation impacting polymorphism, however, have received considerably less attention despite their crucial role in directing crystallisation outcomes. This is mainly due to the lack of available experimental data, as nucleation and growth kinetics of polymorphs are generally difficult to measure. On the one hand, the determination of overall nucleation and growth kinetics through batch experiments suffers from unwanted polymorphic transformations or the absence of experimental conditions under which several polymorphs can be nucleated. On the other hand, growth rates of polymorphs obtained from measurements of single crystals are often only recorded along a few specific crystal dimensions, thus lacking information about overall growth and rendering an incomplete picture of the problem. In this work, we measure the crystal growth kinetics of three polymorphs (I, II and IX) of tolfenamic acid (TFA) in isopropanol solutions, with the intention of providing a meaningful comparison of their growth rates. First, we analyse the relation between the measured growth rates and the crystal structures of the TFA polymorphs. We then explore ways to compare their relative growth rates and discuss their significance when trying to determine which polymorph grows faster. Using approximations for describing the volume of TFA crystals, we show that while crystals of the metastable TFA-II grow the fastest at all solution concentrations, crystals of the metastable TFA-IX become kinetically competitive as the driving force for crystallisation increases. Overall, both metastable forms TFA-II and TFA-IX grow faster than the stable TFA-I.

Geometry and conformation of cyclopropane derivatives having σ-acceptor and σ-donor substituents: a theoretical and crystal structure database study.

The structures of cyclopropane rings which carry σ-acceptor or σ-donor substituents have been studied using density-functional theory (DFT), and mean bond lengths and conformational parameters retrieved from the Cambridge Structural Database. It is confirmed that σ-acceptor substituents, e.g. halogens, generate positive ring bond-length asymmetry in which there is lengthening of the distal bond (opposite to the point of substitution), and shorterning of the two vicinal bonds. This is due to withdrawal of electron density from the cyclopropane 1e'' orbitals, which are bonding for the distal bond and antibonding for the vicinal bonds. For σ-donor substituents such as SiH(3) or Si(CH(3))(3), the DFT and crystal structure data show negative ring bond-length asymmetry (distal bond shortened, vicinal bonds lengthened), owing to electron donation into the 4e' ring orbital, which are also bonding for the distal bond and antibonding for the vicinal bonds. The results also show that -OH substituents induce weak positive asymmetry, but that the effects of methyl or amino substituents are either non-existent or extremely small, certainly too small to measure using crystal structure information.

Complex Growth of Benzamide Form I: Effect of Additives, Solution Flow, and Surface Rugosity.

Understanding crystal growth kinetics is of great importance for the development and manufacturing of crystalline molecular materials. In this work, the impact of additives on the growth kinetics of benzamide form I (BZM-I) crystals has been studied. Using our newly developed crystal growth setup for the measurement of facet-specific crystal growth rates under flow, BZM-I growth rates were measured in the presence of various additives previously reported to induce morphological changes. The additives did not have a significant impact on the growth rates of BZM-I at low concentrations. By comparison to other systems, these additives could not be described as "effective" since BZM-I showed a high tolerance of the additives' presence during growth, which may be a consequence of the type of growth mechanisms at play. Growth of pure BZM-I was found to be extremely defected, and perhaps those defects allow the accommodation of impurities. An alternative explanation is that at low additive concentrations, solid solutions are formed, which was indeed confirmed for a few of the additives. Additionally, the growth of BZM-I was found to be significantly affected by solution dynamics. Changes in some facet growth rates were observed with changes in the orientation of the BZM-I single crystals relative to the solution flow. Of the two sets of facets involved in the growth of the width and length of the crystal, the {10l̅} facets were found to be greatly affected by the solution flow while the {011} facets were not affected at all. Computational fluid dynamics simulations showed that solute concentration has higher gradients at the edges of the leading edge {10l̅} facets, which can explain the appearance of satellite crystals. {10l̅} facets were found to show significant structural rugosity at the molecular level, which may play a role in their mechanism of growth. The work highlights the complexities of measuring crystal growth data of even simple systems such as BZM-I, specifically addressing the effect of additives and fluid dynamics.

Structure prediction, disorder and dynamics in a DMSO solvate of carbamazepine.

We have applied crystal structure prediction methods to understand and predict the formation of a DMSO solvate of the anti-convulsant drug carbamazepine (CBZ), in which the DMSO molecules are disordered. Crystal structure prediction calculations on the 1:1 CBZ:DMSO solvate revealed the generation of two similar low energy structures which differ only in the orientation of the DMSO molecules. Analysis of crystal energy landscapes generated at 0 K suggests the possibility of solvent disorder. A combined computational and experimental study of the changes in the orientation of the DMSO within the crystal structure revealed that the nature of the disorder changes with temperature. At low temperature, the DMSO disorder is static whilst at high temperature the DMSO configurations can interconvert by a 180° rotation of the DMSO molecules within the lattice. This 180° rotation of the DMSO molecules drives a phase change from a high temperature dynamically disordered phase to a low temperature phase with static disorder. Crystallisation of a DMSO solvate of the related molecule epoxycarbamazepine resulted in a different degree of DMSO disorder in the crystal structure, despite the similarity of the carbamazepine and epoxycarbamazepine molecules. We believe consideration of disorder and its contribution to entropy and crystal free energies at temperature other than 0 K is fundamental for the accuracy of future energy rankings in crystal structure prediction calculations of similar solvated structures.

Conformation and geometry of cyclopropane rings having π-acceptor substituents: a theoretical and database study.

The 3e' orbitals of cyclopropane have the correct symmetry to interact with low-lying unoccupied orbitals of π-acceptor substituents and maximum overlap occurs when the two orbital systems are parallel, i.e. when the π-acceptor bisects the ring in projection down the substituent bond. Since the cyclopropyl group is a common component of active pharmaceutical and agrochemical ingredients, it is important that these strong conjugative interactions are well modelled by computational techniques, and clearly represented in experimental crystal structures. Here we show that torsion angle distributions derived from crystal structure data in the Cambridge Structural Database are in excellent correspondence with torsional energy profiles computed using density functional theory (DFT) for a range of substituents: -COOR, -CONR(2), -NO(2), vinyl and phenyl. We also show that crystal structure information is invaluable in modelling conformations of compounds that contain multiply substituted rings, where steric interactions require some substituents to adopt energetically disfavoured conformations. Further, conjugative interactions with π-acceptors lead to significant asymmetry in the cyclopropane ring bond lengths and again the experimental and computational results are in excellent agreement. Such asymmetry effects are additive, and this explains bond-length variations in cyclopropane rings bearing two or more π-acceptor substituents.

Towards crystal structure prediction of complex organic compounds--a report on the fifth blind test.

Following on from the success of the previous crystal structure prediction blind tests (CSP1999, CSP2001, CSP2004 and CSP2007), a fifth such collaborative project (CSP2010) was organized at the Cambridge Crystallographic Data Centre. A range of methodologies was used by the participating groups in order to evaluate the ability of the current computational methods to predict the crystal structures of the six organic molecules chosen as targets for this blind test. The first four targets, two rigid molecules, one semi-flexible molecule and a 1:1 salt, matched the criteria for the targets from CSP2007, while the last two targets belonged to two new challenging categories - a larger, much more flexible molecule and a hydrate with more than one polymorph. Each group submitted three predictions for each target it attempted. There was at least one successful prediction for each target, and two groups were able to successfully predict the structure of the large flexible molecule as their first place submission. The results show that while not as many groups successfully predicted the structures of the three smallest molecules as in CSP2007, there is now evidence that methodologies such as dispersion-corrected density functional theory (DFT-D) are able to reliably do so. The results also highlight the many challenges posed by more complex systems and show that there are still issues to be overcome.