Solid state chemistry of hydrate forming compounds

Polymorphism presents complex issues for the pharmaceutical industry from processing, regulatory, patenting and stability perspectives. It can be further challenging to control the same form throughout processing and development when it has the capacity to form a hydrate. Incorporation of water into the crystal lattice contributes to significant differences in solubility, stability and bioavailability of the active pharmaceutical ingredient (API). During processing and formulating steps, water is used in many procedures such as, recrystallisation, wet granulation, aqueous coating lyophilisation etc. This can trigger anhydrous to hydrate conversion and could be detrimental for bioavailability and stability of the product. The factors responsible for this type of transition such as, role of solvent, activity of solvent, thermodynamic stability of different forms, equilibrium conditions, processing induced transformations are investigated. Theophylline, a channel hydrate, is chosen as a model compound which exhibits both polymorphs and solvates. The value of water activity at which the theophylline monohydrate is thermodynamically stable form was investigated using solubility, cooling crystallisation and slurry experiments and found to be aw 2: 0.70 at 25 QC. Full characterisation of the solid state chemistry of theophylline has resulted in the discovery of a new, previously unreported, anhydrous form of theophylline, called Form IV. Using solubility, crystallisation, slurrying and thermal experiments, Form IV was found to be thermodynamically more stable than the currently known stable form, Form H. The crystal structure of Form IV and Form I was determined by single crystal :X-Ray diffraction technique. The crystal structures for Form IV and Form I are deposited in Cambridge Structural Database (CSD) with reference code BAPLOT03 and BAPLOT04 respectively. The experimentally observed stability behaviour was correlated with the structural features of solid forms and also with the energy calculations. The kinetic ally stable Form H serves as the intermediate for polymorphic and hydrate-anhydrate transformations as the catemer motif observed in Form II can easily propagate by forming a strong and directional hydrogen bonds. In contrast, the dimer of theophylline molecules as observed in Form IV needs the presence of solvent to link through other dimers only by weak interactions. This results in the generation of Form IV only via solvent mediated transformations. Solid state chemistry of hydrate forming compounds Theophylline has also been used here as a model compound to study eo crystallisation with various saturated, dicarboxylic acids. A new, eo crystal of theophylline with adipic acid was generated and using thermal methods and PXRD, the stoichiometry (1 :2, adipic acid: theophylline) is confirmed. The complex hydration-dehydration behaviour of theophylline was investigated. The samples subjected to different pharmaceutical processing conditions for hydration-dehydration, generated various .intermediate phases suggesting multiple dehydration mechanisms and the potential of phase transformations during processing of such kind of hydrate forming compounds. The sensitivity of thermal methods over other bulk methods such as PXRD, in detecting a small amount of phase impurity, has been highlighted.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

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: FIH and FV. Heat capacities have been determined by temperature-modulated DSC for 4 polymorphs: FIL, FIH, 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 FIH 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 FIH 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 FIL and FIH 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\u27s law, and all van\u27t 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. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.ACCEPTEDpeer-reviewe

Solid Forms, Crystal Habits, and Solubility of Danthron

The polymorphism, crystal habits, and solubility of 1,8-dihydroxyanthraquinone (danthron) were investigated in acetic acid, acetone, acetonitrile, <i>n</i>-butanol, and toluene. The solubility was determined for the commercially available form (FI) from 293.15 K to 318.15 K by the gravimetric method. The influence of solvents on crystal habit and polymorphic form has been investigated. Three different crystal habits of danthron were obtained from slow evaporation and cooling experiments. By evaporation, thin squares of FI were obtained from <i>n</i>-butanol and toluene solutions while both FI and fine needles of FII were obtained from acetone and acetonitrile solutions. In addition, needle-shaped solvate crystals were obtained from acetic acid solutions and the structure of the solvate was solved by single crystal X-ray diffraction. From cooling crystallization experiments, mixtures of FI and FII were often obtained from various solvents, but FI and FII possess distinct habits which can be easily distinguished by visual comparison. Slurry conversion experiments have established that FI is the thermodynamically stable polymorph of danthron at ambient conditions. Differntial scanning calorimetry (DSC) and high-temperature powder X-ray diffraction (PXRD) have shown that both FI and FII will transform into a high-temperature form (FIV) around 435 K to 439 K before this form melts at 468.5 K. FI, FII, and FIV have been characterized by transmission and high-temperature PXRD, scanning electron microscopy, infrared spectrometry, Raman spectrometry, thermogravimetric analysis, and DSC. The solubility of danthron FI in the pure organic solvents of the present work and in the temperature range investigated is below 4.3 % by weight and decreases in the order toluene, acetone, acetonitrile, and <i>n</i>-butanol

Solid State Transformations Mediated by a Kinetically Stable Form

The anhydrous forms of theophylline and the stability relationships with the monohydrate, Form M, are characterized. Form II, kinetically stable at room temperature and considered as the most stable form during the 70-year history of theophylline usage, is observed to act as an intermediary for conversions between other forms. Form IV, the thermodynamically stable form at room temperature, is shown to be enantiotropically related to Form II and undergoes a solid state transition on heating. The enantiotropic relationship between Forms II and I was investigated, and it was established that a Form II to I transition is observed only in samples generated using specific methods. Form III was found to be a high energy solid form which can only be generated by dehydration of the hydrate. Upon heating, Form III shows an exothermic transition to Form II. Upon rehydration, Form III is extremely hygroscopic and converts initially to Form II and then to Form M. The complexity of anhydrate–hydrate relationships is illustrated, and the influence of sample history on batch purity is shown, which in turn may influence solid form transformations

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

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: FIH and FV. Heat capacities have been determined by temperature-modulated DSC for 4 polymorphs: FIL, FIH, 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 FIH 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 FIH 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 FIL and FIH 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. (C) 2016 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved

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 < ethyl acetate < n-propanol < toluene. The combined DFT and MD modelling results show that in acetonitrile, ethyl acetate and n-propanol the nucleation difficulty is a function of the strength of solvent-solute interaction, with emphasis on the interaction with specific H-bonding polar sites of importance in the crystal structure. A clear exception from this rule is the most difficult nucleation in toluene despite the weakest solvent-solute interactions. However molecular dynamics modelling predicts that tolbutamide assumes an intramolecularly H-bonded conformation in toluene, substantially different from and more stable than the conformation in the crystal structure, and thus presenting an additional barrier to nucleation. This explains why nucleation in toluene is the most difficult and why the relatively higher propensity for aggregation of tolbutamide molecules in toluene solution, as observed with FTIR spectroscopy, does not translate into easier nucleation. Thus, our combined experimental and molecular modelling study suggests that the solvent can influence on the nucleation not only via differences in the desolvation but also through the influence on molecular conformation

Probing crystal nucleation of fenoxycarb from solution through the effect of solvent

Induction time experiments, spectroscopic and calorimetric analysis, and molecular modelling were used to probe the influence of solvent on the crystal nucleation of fenoxycarb (FC), a medium-sized, flexible organic molecule. 800 induction times covering a range of supersaturations and crystallisation temperatures in four different solvents were measured to elucidate the relative ease of nucleation. To achieve similar induction times, the required thermodynamic driving force, RTlnS, increases in the order: ethyl acetate < toluene < ethanol < isopropanol. This is roughly matched by the order of interfacial energies calculated using the Classical Nucleation Theory. Solvent-solute interaction strengths were estimated using three methods: solvent-solute enthalpies derived from calorimetric solution enthalpies, solvent-solute interactions from Molecular Dynamics simulations, and the FTIR shifts in the carbonyl stretching corresponding to the solvent-solute interaction. The three methods gave an overall order of solvent-solute interactions increasing in the order: toluene < ethyl acetate < alcohols. Thus, with the exception of FC in toluene, it is found that the nucleation difficulty increases the stronger the solvent binds the solute

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 mm, 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