Mesoscale Clusters in the Crystallisation of Organic Molecules.

The early stages of the molecular self-assembly pathway leading to crystal nucleation have a significant influence on the properties and purity of organic materials. This mini review collates the work on organic mesoscale clusters and discusses their importance in nucleation processes, with a particular focus on their critical properties and susceptibility to sample treatment parameters. This is accomplished by a review of detection methods, including dynamic light scattering, nanoparticle tracking analysis, small angle X-ray scattering, and transmission electron microscopy. Considering the challenges associated with crystallisation of flexible and large-molecule active pharmaceutical ingredients, the dynamic nature of mesoscale clusters has the potential to expand the discovery of novel crystal forms. By collating literature on mesoscale clusters for organic molecules, a more comprehensive understanding of their role in nucleation will evolve and can guide further research efforts.

Investigation into the Nucleation of the p-Hydroxybenzoic Acid:Glutaric Acid 1:1 Cocrystal from Stoichiometric and Non-Stoichiometric Solutions.

The nucleation in the p-hydroxybenzoic acid:glutaric acid 1:1 cocrystal (PHBA:GLU) system has been investigated in stoichiometric and non-stoichiometric acetonitrile solutions by induction time experiments. Utilizing the ternary phase diagram, the supersaturated non-stoichiometric solutions were created with compositions along the invariant point boundary lines. In all cases, the PHBA:GLU cocrystal was the nucleating phase, even though the non-stoichiometric solutions were also supersaturated with respect to the pure solid phases. The nucleation of the cocrystal from the mixed solutions is found to be more difficult than the nucleation of the pure compounds from the respective pure solutions, as captured by lower pre-exponential factors (A). However, if the driving force is defined per reactant molecule instead of per heterodimer, the cocrystal nucleation difficulty is close to that of the more difficult-to-nucleate pure compound. The difference in nucleation difficulty of the cocrystal from stoichiometric and non-stoichiometric solutions was captured by differences in the interfacial energy, while the pre-exponential factor remained unchanged. Apart from the pure GLU system, the relation between the experimentally determined pre-exponential factors for the different systems correlates with calculated values using theoretical expressions for volume-diffusion and surface-integration control.

Characterization and Crystal Nucleation Kinetics of a New Metastable Polymorph of Piracetam in Alcoholic Solvents.

A new polymorph of the drug active pharmaceutical ingredient piracetam (Form VI) has been discovered and characterized by X-ray powder diffraction (PXRD), solid-state Raman, attenuated total reflectance infrared spectroscopy, and differential scanning calorimetry. The PXRD diffractogram of Form VI shows a distinct peak at 24.2° (2θ) that distinguishes it from the previously known polymorphs and solvates. Form VI is metastable with respect to the previously known polymorphs Form II and Form III; in ethanol solution at 288 K, Form VI transforms into Form II within 15 min, while in isopropanol solution Form VI is kinetically stable for at least 6 h. A total of 1200 crystal nucleation induction time experiments of piracetam in ethanol and isopropanol solutions have been conducted, in sets of 40-80 repeat experiments carried out at different temperatures and solute concentrations. Each solution nucleated as a single polymorph, and each set of repeat experiments resulted in different proportions of Form II, Form III, and Form VI, with Form VI dominating at low nucleation temperatures and Form II at higher nucleation temperatures. The induction time data for Form VI at 288 K have been evaluated within the framework of the classical nucleation theory. At equal driving force, nucleation of Form VI is less obstructed in ethanol than in isopropanol, as captured by a lower interfacial energy and higher pre-exponential factor in ethanol. The proportion of Form VI obtained at a comparable driving force increases in the order ethanol < isopropanol.

Pure Curcumin Spherulites from Impure Solutions via Nonclassical Crystallization.

Crystallization experiments performed with highly supercooled solutions produced highly pure (>99 wt %) and highly crystalline mesocrystals of curcumin from impure solutions (∼22% of two structurally similar impurities) in one step. These mesocrystals exhibited a crystallographic hierarchy and were composed of perfectly or imperfectly aligned nanometer-thick crystallites. X-ray diffraction and spectroscopic analysis confirmed that the spherulites are a new solid form of curcumin. A theoretical hypothesis based on particle aggregation, double nucleation, and repeated secondary nucleation is proposed to explain the spherulite formation mechanism. The experimental results provide, for the first time, evidence for an organic molecule to naturally form spherulites without the presence of any stabilizing agents. Control experiments performed with highly supercooled pure solutions produced spherulites, confirming that the formation of spherulites is attributed to the high degree of supercooling and not due to the presence of impurities. Likewise, control experiments performed with a lower degree of supercooling produced impure crystals of curcumin via classical molecular addition mechanisms. Collectively, these experimental observations provide, for the first time, evidence for particle-mediated crystallization as an alternate and efficient method to purify organic compounds.

Nucleation of the Theophylline:Salicylic Acid 1:1 Cocrystal.

The nucleation behavior of the theophylline-salicylic acid 1:1 (THP:SA) cocrystal in chloroform has been investigated and compared with the corresponding behavior of the pure compounds. Induction times have been determined at different supersaturations at 10 °C under each condition in approximately 40-80 repetition experiments in 20 mL vials. Nucleation times, extracted from the median induction times by accounting for a nucleus growth time, have been used to determine the interfacial energy and the pre-exponential factor within the classical nucleation theory. Results show that the cocrystal at equal driving force has a longer nucleation time, or to reach equal nucleation time, the cocrystal requires a higher driving force. Pure theophylline is easier to nucleate than pure salicylic acid, despite the latter having a smaller molecular size, higher solubility, and is expected to form dimers already in the solution. The cocrystal is found to have an interfacial energy in between the respective values for the pure compounds. However, the higher molecular volume of the cocrystal, taken as the volume of the 1:1 theophylline-salicylic acid assembly, leads to the highest nucleation work, which, together with a low pre-exponential factor, explains why the cocrystal is the most difficult to nucleate. The experimentally extracted pre-exponential factor of the cocrystal is very similar to that of THP, and similar trends are observed from theoretical expressions of volume-diffusion- and surface-integration-controlled nucleation, respectively.

Thermodynamics of the Enantiotropic Pharmaceutical Compound Benzocaine and Solubility in Pure Organic Solvents.

The thermodynamic relationship between FI and FII of ethyl 4-aminobenzoate (benzocaine) has been investigated. Slurry conversion experiments show that the transition temperature below which FI is stable is located between 302 K-303 K (29 °C-30 °C). The polymorphs FI and FII have been characterised by infrared spectroscopy (IR), Raman spectroscopy, transmission powder X-ray diffraction (XRPD) and differential scanning calorimetry (DSC). The isobaric solid state heat capacities have been measured by DSC. The quantitative thermodynamic stability relationship has been determined in a comprehensive thermodynamic analysis of the calorimetric data. The solubility of both polymorphs has been determined in eight pure organic solvents over the temperature range 278 K-323 K by a gravimetric method. The mole fraction solubility of benzocaine decreases in the order: 1,4-dioxane, acetone, ethyl acetate, chloroform, acetonitrile, methanol, n-butanol and toluene. Comparison with the determined activity of solid benzocaine forms shows that negative deviation from Raoult's law ideality is found in dioxane, acetone and ethyl acetate solutions, and positive deviation in solutions of the other investigated solvents.

Solubility and thermodynamic analysis of ketoprofen in organic solvents.

The solubility of the racemic solid phase of ketoprofen (KTP) in methanol, ethanol, isopropanol, butanol, acetonitrile, ethyl acetate, 1,4-dioxane and toluene has been determined between 273 and 303 K by a gravimetric method. FTIR and Raman spectroscopy, SEM and PXRD, have been used to characterise the solid phase. The melting data and heat capacity of solid and melt have been determined by DSC, and used to estimate fusion thermodynamics and the activity of the solid phase as functions of temperature. Empirical and semi-empirical models have been fitted to experimental solubility data. The solution activity coefficients reveal positive deviation from ideality in all solvents except for in dioxane, and very close to ideality in methanol. The solubility is fairly high in the alcohols but decrease with increasing hydrocarbon chain. Generally and due to the presence of the carboxylic acid group, KTP is more readily dissolved in polar protic solvents, followed in order by polar aprotic and non-polar solvents. However, the highest solubility is found in dioxane, classified as a non-polar solvent, but notably though the molecule having two strong hydrogen bond accepting functionalities, and no hydrogen bond donation capability.

Solubility of Two Polymorphs of Tolbutamide in n-Propanol: Comparison of Methods.

The solid-liquid solubility of two polymorphs of the title compound has been measured in n-propanol over the temperature range (278 K-303 K) by an isothermal, gravimetric method and a low heating rate polythermal method. Due to marked differences in the settling behavior of crystals of the two polymorphs in the investigated solvent, it is found that the low heating rate polythermal method gives the overall best performance for this particular system. Systematic slurry conversion experiments show that FII is the stable polymorph over the investigated temperature range (268 K-308 K). Solubility data for both polymorphs is well correlated, and has been extrapolated to the melting point, by a previously proposed semi-empirical regression model based on solid-phase calorimetric data. The system exhibits a marked positive deviation from Raoult's law, with solute activity coefficients at equilibrium decreasing with increasing temperature.

Solid and Solution State Thermodynamics of Polymorphs of Butamben (Butyl 4-Aminobenzoate) in Pure Organic Solvents.

The solubility of butamben has been measured gravimetrically in pure methanol, 1-propanol, 2-propanol, 1-butanol, and toluene over the temperature range 268-298 K. Polymorph transition and melting temperatures, associated enthalpy changes, and the heat capacity of the solid forms and the supercooled melt have been measured by differential scanning calorimetry. Based on extrapolated calorimetric data, the Gibbs energy, enthalpy and entropy of fusion, and the activity of solid butamben (the ideal solubility) have been calculated from below ambient temperature up to the melting point. Activity coefficients of butamben at equilibrium in the different solvents have been estimated from solubility data and the activity of the solid, revealing that all investigated systems exhibit positive deviation from Raoult's law. Solubility data are well correlated by a semiempirical regression model. On a mass basis, the solubility is clearly higher in methanol than in the other solvents, but mole fraction solubilities are very similar across all 5 solvents. The 2 known polymorphs are enantiotropically related, and the transition point is located at 283 K. Polymorph interconversions occur within 0.3 K of the transition point even in the solid state, and the 2 forms exhibit strong similarities in investigated properties.

Solute clustering in undersaturated solutions - systematic dependence on time, temperature and concentration.

Molecular clustering and solvent-solute interactions in isopropanol solutions of fenoxycarb have been thoroughly and systematically investigated by dynamic light scattering, small-angle X-ray scattering, and nanoparticle tracking, supported by infrared spectroscopy and molecular dynamics simulations. The existence of molecular aggregates, clusters, ranging in size up to almost a micrometre is clearly recorded at undersaturated as well as supersaturated conditions by all three analysis techniques. The results systematically reveal that the cluster size increases with solute concentration and time at stagnant conditions. For most concentrations the time scale of cluster growth is of the order of days. In undersaturated solutions the size appears to eventually reach a maximum value, higher the higher the concentration. Below a certain concentration threshold clusters are significantly smaller. Clusters are found to be smaller in solutions pre-heated at a higher temperature, which offers a possible explanation for the so-called "history of solution" effect. The cluster distribution is influenced by filtration through membranes with a pore size of 0.1 µm, offering an alternative explanation for the "foreign particle-catalysed nucleation" effect. At moderate concentrations larger clusters appear to be sheared into smaller ones, but the original size distribution is rapidly re-established. At higher concentrations, although still well below solubility, the cluster size as well as solute concentration are strongly affected, suggesting that larger clusters contain at least a core of more organized molecules not able to pass through the filter.

Crystal Nucleation of Tolbutamide in Solution: Relationship to Solvent, Solute Conformation, and Solution Structure.

The influence of the solvent in nucleation of tolbutamide, a medium-sized, flexible and polymorphic organic molecule, has been explored by measuring nucleation induction times, estimating solvent-solute interaction enthalpies using molecular modelling and calorimetric data, probing interactions and clustering with spectroscopy, and modelling solvent-dependence of molecular conformation in solution. The nucleation driving force required to reach the same induction time is strongly solvent-dependent, increasing in the order: acetonitrile

Modelling and understanding powder flow properties and compactability of selected active pharmaceutical ingredients, excipients and physical mixtures from critical material properties.

The development of solid dosage forms and manufacturing processes are governed by complex physical properties of the powder and the type of pharmaceutical unit operation the manufacturing processes employs. Suitable powder flow properties and compactability are crucial bulk level properties for tablet manufacturing by direct compression. It is also generally agreed that small scale powder flow measurements can be useful to predict large scale production failure. In this study, predictive multilinear regression models were effectively developed from critical material properties to estimate static powder flow parameters from particle size distribution data for a single component and for binary systems. A multilinear regression model, which was successfully developed for ibuprofen, also efficiently predicted the powder flow properties for a range of batches of two other active pharmaceutical ingredients processed by the same manufacturing route. The particle size distribution also affected the compactability of ibuprofen, and the scope of this work will be extended to the development of predictive multivariate models for compactability, in a similar manner to the approach successfully applied to flow properties.

Thermodynamic Stability Analysis of Tolbutamide Polymorphs and Solubility in Organic Solvents.

Melting temperatures and enthalpies of fusion have been determined by differential scanning calorimetry (DSC) for 2 polymorphs of the drug tolbutamide: FI(H) and FV. Heat capacities have been determined by temperature-modulated DSC for 4 polymorphs: FI(L), FI(H), FII, FV, and for the supercooled melt. The enthalpy of fusion of FII at its melting point has been estimated from the enthalpy of transition of FII into FI(H) through a thermodynamic cycle. Calorimetric data have been used to derive a quantitative polymorphic stability relationship between these 4 polymorphs, showing that FII is the stable polymorph below approximately 333 K, above which temperature FI(H) is the stable form up to its melting point. The relative stability of FV is well below the other polymorphs. The previously reported kinetic reversibility of the transformation between FI(L) and FI(H) has been verified using in situ Raman spectroscopy. The solid-liquid solubility of FII has been gravimetrically determined in 5 pure organic solvents (methanol, 1-propanol, ethyl acetate, acetonitrile, and toluene) over the temperature range 278 to 323 K. The ideal solubility has been estimated from calorimetric data, and solution activity coefficients at saturation in the 5 solvents determined. All solutions show positive deviation from Raoult's law, and all van't Hoff plots of solubility data are nonlinear. The solubility in toluene is well below that observed in the other investigated solvents. Solubility data have been correlated and extrapolated to the melting point using a semiempirical regression model.

Solubility and crystal nucleation in organic solvents of two polymorphs of curcumin.

Two crystal polymorphs of 1,7-bis-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (curcumin) have been obtained by crystallization from ethanol (EtOH) solution. The polymorphs have been characterized by differential scanning calorimetry, infrared spectroscopy, and X-ray powder diffraction and shown to be the previously described forms I and III. The solubility of both polymorphs in EtOH and of one polymorph in ethyl acetate (EA) has been measured between 10°C and 50°C with a gravimetric method. Primary nucleation of curcumin from EtOH solution has been investigated in 520 constant temperature crystallization experiments in sealed, magnetically stirred vials under different conditions of supersaturation, temperature, and agitation rate. By a thermodynamic analysis of the melting data and solubility of form I, the solid-state activity is estimated from 10°C up to the melting point. The solubility is lower in EtOH than in EA, and in both solvents, a positive deviation from Raoult's law is observed. Form I has lower solubility than form III and is accordingly thermodynamically more stable over the investigated temperature interval. Extrapolation of solubility regression models indicates that there should be a low-temperature enantiotropic transition point, below which form I will be metastable. By slurry conversion experiments, it is established that this temperature is below -30°C. All nucleation experiments resulted in the stable form I. The induction time is observed to decrease with increasing agitation rate up to a certain point, and then increase with further increasing agitation rate; a trend previously observed for other compounds. By correlating the induction time data obtained at different supersaturation and temperature, the interfacial energy of form I in EtOH is estimated to be 3.0 mJ/m(2) .

Influence of solvent on crystal nucleation of risperidone.

Over 2100 induction time experiments were carried out for the medium-sized, antipsychotic drug molecule, risperidone in seven different organic solvents. To reach the same induction time the required driving force increases in the order: cumene, toluene, acetone, ethyl acetate, methanol, propanol, and butanol, which reasonably well correlates to the interfacial energies as determined within classical nucleation theory. FTIR spectroscopy has been used to investigate any shifts in the spectra and to estimate the interaction of solute and solvent at the corresponding site. The solution condition has also been investigated by Density Functional Theory (DFT) calculations over (1 : 1) solvent-solute binding interactions at 8 different sites on the risperidone molecule. The DFT computational results agree with the spectroscopic data suggesting that these methods do capture the binding strength of solvent molecules to the risperidone molecule. The difficulty of nucleation correlates reasonably to the DFT computations and the spectroscopic measurements. The results of the different measurements suggest that the stronger the solvent binds to the risperidone molecule in solution, the slower the nucleation becomes.

Analysis of the structure and morphology of fenoxycarb crystals.

In this paper, we have explored the relationship between surface structure and crystal growth and morphology of fenoxycarb (FC). Experimental vs. predicted morphologies/face indices of fenoxycarb crystals are presented. Atomic-scale surface structures of the crystalline particles, derived from experimentally indexed single crystals, are also modelled. Single crystals of fenoxycarb exhibit a platelet-like morphology which closely matches predicted morphologies. The solvent choice does not significantly influence either morphology or crystal habit. The crystal morphology is dominated by the {001} faces, featuring weakly interacting aliphatic or aromatic groups at their surfaces. Two distinct modes of interaction of a FC molecule in the crystal can be observed, which appear to be principal factors governing the microscopic shape of the crystal: the relatively strong collateral and the much weaker perpendicular bonding. Both forcefield-based and quantum-chemical calculations predict that the aromatic and aliphatic terminated {001} faces have comparably high stability as a consequence of weak intermolecular bonding. Thus we predict that the most developed {001} surfaces of fenoxycarb crystals should be terminated randomly, favouring neither aliphatic nor aromatic termination.

Investigating the role of solvent-solute interaction in crystal nucleation of salicylic acid from organic solvents.

In previous work, it has been shown that the crystal nucleation of salicylic acid (SA) in different solvents becomes increasingly more difficult in the order: chloroform, ethyl acetate acetonitrile, acetone, methanol, and acetic acid. In the present work, vibration spectroscopy, calorimetric measurements, and density functional theory (DFT) calculations are used to reveal the underlying molecular mechanisms. Raman and infrared spectra suggest that SA exists predominately as dimers in chloroform, but in the other five solvents there is no clear evidence of dimerization. In all solvents, the shift in the SA carbonyl peak reflecting the strength in the solvent-solute interaction is quite well correlated to the nucleation ranking. This shift is corroborated by DFT calculated energies of binding one solvent molecule to the carboxyl group of SA. An even better correlation of the influence of the solvent on the nucleation is provided by DFT calculated energy of binding the complete first solvation shell to the SA molecule. These solvation shell binding energies are corroborated by the enthalpy of solvent-solute interaction as estimated from experimentally determined enthalpy of solution and calculated enthalpy of cavity formation using the scaled particle theory. The different methods reveal a consistent picture and suggest that the stronger the solvent binds to the SA molecule in solution, the slower the nucleation becomes.

Particle engineering of benzoic acid by spherical agglomeration.

The influence of process conditions on the properties of benzoic acid spherical agglomerates, are investigated. Agglomerates are produced in a fed-batch agitated tank process. Benzoic acid is dissolved in ethanol and the solution is mixed with the bridging liquid, before being fed into an agitated aqueous solution. A broader investigation has been performed using heptane as the bridging liquid, and in further experiments different bridging liquids are compared. The results show that the bridging liquid has an influence on the product properties, with diethyl ether and ethyl acetate being at the extreme end with no agglomerates formed at all. Using any of the other five solvents (chloroform, toluene, heptane, pentane, or cyclohexane) spherical agglomerates are formed, as long as a sufficient amount of the bridging liquid is used. The results show that the particle size and strength increase with increasing amount of bridging liquid, and with decreasing temperature. At amount of bridging liquid producing optimum particle shape, the largest agglomerates are produced when using either cyclohexane operating at 5 °C, or using toluene in a process at 20 °C. The highest particle fracture stress is obtained using toluene as the bridging liquid regardless of temperature. The particle shape depends on the bridging liquid, and becomes completely spherical when toluene or pentane is used. For four of the solvents the particle morphology improves with decreasing temperature, but for cyclohexane the result is the opposite. By continued agitation beyond the completion of the feeding, particle size and strength gradually increases and also the shape gradually becomes more spherical. High compressibility and low elastic recovery suggest that the particles are favorable for direct tabletting. The results are analyzed and discussed against capillary theory and granulation mechanisms.

On the mechanisms of formation of spherical agglomerates.

Spherical agglomerates of benzoic acid have been successfully prepared by semi-batch, agitated vessel, drowning-out crystallization in water-ethanol-toluene mixtures. Benzoic acid is dissolved in ethanol, toluene is added and this mixture is fed at constant rate to the agitated crystallizer containing water. The influence of the amount of bridging liquid and the feeding rate on the product particle size distribution, morphology, and mechanical compression characteristics have been investigated. Compression characteristics for single agglomerates are compared with data on bed compression. With increasing amount of bridging liquid the particle size and strength increases and morphology improves. Particle size decreases and the fracture force increases with increasing feeding rate but the morphology remains unchanged. Using toluene as opposed to chloroform as the bridging liquid leads to improved product properties. Experiments have also been performed to reveal the mechanisms of the formation of the agglomerates. The results show that along the course of the process the properties of the particles change gradually but substantially. Particle size and number increases along with increasing feed. The spherical shape does not appear immediately but develops gradually, and is shown to be very much the result of the agitation of the slurry.

Prediction of solubility curves and melting properties of organic and pharmaceutical compounds.

The relationships between solubility, temperature dependence of solubility, melting temperature and melting enthalpy are investigated for the purpose of finding relations that can significantly reduce the need for experimental work in the selection of the solvent for processing of organic fine chemicals and pharmaceuticals. The relationships are investigated theoretically and by evaluation of experimental data for 41 organic and pharmaceutical compounds comprising a total of 115 solubility curves in organic and aqueous solvents. The work considers (i) selection of the equation for correlation of solubility data based on thermodynamic considerations and ability to predict melting properties of the solute from solubility data, (ii) prediction of the temperature dependence of solubility, and (iii) prediction of solubility curves in new solvents. While it is a simple task to find an equation to obtain a decent fit of experimental solubility data, it is more challenging to find relations that are sufficiently sound thermodynamically to allow for extrapolation to the melting temperature. However, with a proper choice of equation it is shown that the melting temperature of the solute can readily be predicted from solubility data in organic solvents (average accuracy of -5K, standard deviation of 26K). Relationships are identified by which the entire solubility curve can be predicted of the compound in a new solvent using only the melting properties and a single solubility data point in that solvent.