Polymorphic Crystal Forms Research Articles

Toward Polymorph Control in an Inorganic Crystal System by Templated Nucleation at a Microdroplet Liquid Interface: Potassium Hexacyanoferrate(II) Trihydrate

Potassium hexacyanoferrate(II) trihydrate (KFCT) is known to manifest multiple structure types under practical conditions of crystal growth, including a monoclinic modification which is stable at room temperature and a metastable tetragonal form. Its rich polytypic nature renders it an ideal model inorganic crystal for studies of the influence of ordered structures upon the nucleation of differing crystal forms. We have utilized a microdroplet-based crystallization method to investigate the influence of self-assembled surfactant monolayers (octadecanol, stearic acid, and octadecylamine (ODA)) at a water-decanol interface upon the crystal nucleation behavior of KFCT at the isolated microdroplet level. Our results indicate that markedly different habits can be selectively nucleated, depending upon the choice of surfactant and temperature. The crystals of differing habits were analyzed by polarized light microscopy and micro-Raman spectroscopy. We have demonstrated that a droplet crystallization platform promises control of the nucleation outcome, even in a crystal system where the polymorphic crystal forms have only the most delicate energetic differences, since confinement to isolated droplets ensures single nucleation events and avoids interconversion of polymorphic forms.

Evaluation of reversible polymorphic phase transitions by thermal analysis.

Crystalline states of 1,2-dihydro-6-neopentyl-2-oxonicotinic acid, an investigational antidiabetic drug, were evaluated by thermal analyses. Two polymorphs were detected for the drug, Form I (m.p. 193 degrees C) and Form II (m.p. 196 degrees C). Interconversion of the polymorphs upon cyclic solid-melt transitions provided confirmation of the crystal forms. Solidification of the melt was observed to occur either at 162 or 182 degrees C with the formation of Form I or Form II crystals, respectively. Form I underwent partial conversion to Form II upon heating at 10 degrees C min-1 when nucleating crystals of Form II were present in the sample. Differential scanning calorimetry (DSC) thermograms were recorded for different lots of the drug, solvent-recrystallized samples, and a series of known mixtures of Form I and II polymorphs. The study illustrates the usefulness of cyclic heat-cool studies to characterize polymorphic crystal forms of drugs.

Effect of drawing on the molecular orientation, polymorphism, and properties of melt‐spun nanocomposite fibers based on nylon 6 with polyhedral oligomeric silsesquioxane, montmorillonite, and their combination

AbstractIn this work, binary and ternary nanocomposite systems based on nylon 6 with montmorillonite (MMT), polyhedral oligomeric silsesquioxane (POSS), and their combination were prepared using a melt‐compounding process. In the transmission electron microscope (TEM) images, the MMT was found to be generally well dispersed in all materials resulting in its good chemical compatibility with nylon 6, affording intercalated disordered microstructures. On the other hand, the TEM images showed that POSS formed micron‐size crystalline agglomerates possibly resulting from a lack in chemical compatibility with nylon 6. These nanocomposite systems were melt‐spun into fibers, and the relevant structure–property relationships that occur during the cold drawing process was established by correlating the tensile properties to the changes in crystallinity, polymorphic crystal forms, and molecular orientation. The properties of the resulting fibers were found to be rather skewed and significantly affected by the polymer/nanoparticles interface. The agglomeration of POSS and POSS–MMT particles coupled with the weak nylon 6/POSS interface, reflected on the tensile properties of the nylon 6/POSS and nylon 6/MMT‐POSS fibers which underperformed. Some nanocomposite fiber systems offered significant improvements in modulus without excessively compromising the extensibility of the fibers. POLYM. COMPOS., 2011. © 2011 Society of Plastics Engineers

Polymorphic Crystal Approach to Changing the Emission of [AuCl(PPh3)2], Analyzed by Direct Observation of the Photoexcited Structures by X-ray Photocrystallography

The photoexcited charge-transferred state of [AuCl(PPh(3))(2)] in a novel polymorphic crystal form was directly observed by X-ray photocrystallographic analysis. Its photoexcited state was completely different from the one generated in the known crystal of [AuCl(PPh(3))(2)]; the photoexcited bond-shrunk state was generated in the known crystal. This difference in the generated photoexcited state was clearly reflected by the difference in emission color. While the known crystal form showed green phosphorescence, the novel form showed blue phosphorescence under UV irradiation. The difference in the generated photoexcited state was due to the differences in steric hindrance in the crystal; bond shortening by photoexcitation was sterically allowed in the known form, while on the other hand, it was restricted in the novel form. Therefore, instead of the bond-shrunk state, the charge-transferred excited state became the lowest triplet state, and the emission color changed from green to blue (i.e., a blue shift of the emission wavelength was observed). These results mean that the photoexcited structure and the emission color of [AuCl(PPh(3))(2)] can be controlled by designing the molecular environment in the crystal.

Transformation of Monohydrate into Anhydrous Form of Risedronate Monosodium in Methanol−Water Mixture

The transformation of a monohydrate into an anhydrous form of risedronate monosodium (RS) in a methanol and water mixture was investigated. The phase transformation was detected by monitoring the number of particles, particle size, and shape. At the same time, polymorphic forms of crystals were identified by various offline techniques such as XRPD, TGA, and DSC. The kinetics of phase transformation was found to be controlled by three-dimensional nuclear growth. The reaction of water in the solvent mixture was a main factor determining the stability of anhydrate and monohydrate forms. The time required for phase transformation was strongly affected by temperature and agitation rate. The phase transformation could be successfully determined in real time by using an in situ particle measurement system.

Endogenous Nonionic Saturated Monoethanolamide Lipids: Solid State, Lyotropic Liquid Crystalline, and Solid Lipid Nanoparticle Dispersion Behavior

The n-acylethanolamides (NAEs) are a family of naturally occurring monoethanolamide containing lipids that display a variety of interesting biological properties. In this study, some physicochemical properties of a series of saturated monoethanolamide lipids with increasing hydrocarbon chain length (lauroyl, myristoyl, palmitoyl, and stearoyl) have been investigated. Temperature induced phase transitions for these NAEs indicate that both the monoethanolamide headgroups and the unsaturated hydrophobic tails play a role in the melting behavior of these lipids. All four lipids examined demonstrate the presence of at least three different polymorphic crystal forms. Transitions in crystal structure can be induced via heating and visualized with polarized optical microscopy. At room and physiological temperature, the four NAEs are solid lamellar crystalline materials. All four molecules form lyotropic liquid crystalline phases in water, albeit at relatively high temperatures, including the lamellar liquid crystalline phase and at least two isotropic phases. Lamellar crystalline palmitoyl monoethanolamide was dispersed as solid lipid nanoparticles (SLNs). The cytotoxicity of these SLNs toward human mammary epithelial cells (HMEpiC) and the MCF7 breast cancer cell line was assessed at physiological temperature. The palmitoyl monoethanolamide SLNs showed little to no toxicity to the HMEpiC even at a concentration of 30 microM. At concentrations above 3 microM, the HMEpiC population was reduced by less than 15%, while the MCF7 population was reduced by approximately 20-30%. The endogenous nature and natural medicinal properties make this series of lipids ideal candidates for further investigation as solid lipid nanoparticle drug delivery systems.

Theoretical interpretation of the infrared spectra of the hydrogen bond

A theory is presented which describes the energy and intensity distribution in the infrared spectra of the hydrogen-bonded systems. The effect of Fermi resonance on the form of spectra is studied for an individual hydrogen bond and for a cyclic dimer. The theory is used to calculate the IR transitions in the spectra of hydrogen-bonded crystals, including the deuterium effect and changes due to different polymorphic forms of crystals.

Importance of Vibrational Zero-Point Energy Contribution to the Relative Polymorph Energies of Hydrogen-Bonded Species

The relative stability of polymorphic crystal forms is a challenging conceptual problem of considerable technical interest. Current estimates of relative polymorph energies concentrate on lattice energy. In this work the contribution of differences in zero-point energy and vibrational enthalpy to the enthalpy difference for polymorphs is investigated. The specific case investigated is that of α- and γ-glycine, for which the experimental enthalpy difference is known. Periodic lattice density functional theory (DFT) computations are used to provide the vibrational spectrum at the Γ-point. It is confirmed that these methods provide reasonable descriptions of the inelastic neutron scattering spectra of these two crystals. It is found that the difference in the zero-point energy is about 1.9 kJ/mol and that the vibrational thermal population difference is 0.9 kJ/mol in the opposite sense. The overall vibrational contributions to the enthalpy difference are much larger than the observed value of ca. 0.3 kJ/mol....

Molecular Self‐Assembly of Macroporous Parallelogrammatic Pipes

The pipes, the pipes are calling: Organic parallelogram-shaped pipes of micrometer dimensions have been obtained by simply allowing drops of a solution of low-molecular-weight compounds to evaporate. This unique structure is formed by self-templated crystal growth during the evaporation. The mechanism of formation involves two polymorphic crystal forms in dynamic nonequilibrium conditions.

Evaluation of cooling strategies for pumping of milk – Impact of fatty acid composition on free fatty acid levels

Cooling strategies for pumping of raw milk were evaluated. Milk was pumped for 450 s at 31 degrees C, or pumped after cooling to 4 degrees C and subsequently subjected to various incubation times. Two types of milk were used; i.e. milk from cows fed a diet high in saturated fat supplements resulting in significantly larger milk fat globules than the other type of milk which comes from cows fed a low-fat diet that stimulates high de novo fat synthesis. The content of liquid fat was determined by low-field 1H NMR, which showed that milk from cows given the saturated fat diet also contained less liquid fat at both 4 degrees and 31 degrees C than the other type of milk. This can be ascribed to the differences in the fatty acid composition of the milk as a result of the fatty acid composition of the diets. After pumping of the milk at 31 degrees C, measurement of fat globule size distribution revealed a significant coalescence of milk fat globules in the milk obtained from the saturated fat diet due to pumping. Pumping at 4 degrees C or pumping the other type of milk did not result in coalescence of milk fat globules. Formation of free fatty acids increased significantly in both types of milk by pumping at 31 degrees C. Cooling the milk to 4 degrees C immediately before pumping inhibited an increased content of free fatty acids. However, when the milk was incubated at 4 degrees C for 60 min after cooling and then subjected to pumping, a significant increase in the formation of free fatty acids was observed in both types of milk. It is suggested that this increase in free fatty acids is caused by transition of polymorphic crystal forms or higher level of attached lipoprotein lipases to the milk fat globule before pumping.

Solid-state characterization of chloroprocaine hydrochloride

Chloroprocaine hydrochloride (2-CPCHC) is a local anaesthetic agent of the ester type preferentially used for epidural anaesthesia. The compound, official in the USP, was found to exist in two polymorphic crystal forms which have been characterized by thermomicroscopy, differential scanning calorimetry (DSC), pycnometry, FTIR-, FT-Raman-spectroscopy as well as X-ray powder diffractometry. Based on these data the relative thermodynamic stability of the two forms was determined and is represented in a semi-schematic energy/temperature diagram. Mod. I° is the thermodynamically stable form at room temperature. This form is present in commercial products and can be crystallized from ethanol. Mod. II can be obtained by annealing the supercooled melt in a temperature range between 100 and 130°C. Upon heating mod. II exhibits an exothermic phase transition (ΔtrsHII-I: -5.0±0.5 kJ mol-1) at about 134°C to mod. I° (melting point 175°C, ΔfusHI: 46.6±0.6 kJ mol-1). The exothermic transformation of mod. II to mod. I° confirms that mod. I° is thermodynamically stable in the entire temperature range (heat of transition rule) whereas mod. II is monotropically related to mod. I°, i.e. is metastable at all temperatures below its melting point. Mod. II is of low kinetic stability at room temperature and the transformation to mod. I° starts within a few minutes at room temperature. The N-H band in the infrared spectrum of mod. I° (3433 cm-1) lies at significantly higher wavenumbers than that of mod. II (3413 cm-1) indicating differences in the hydrogen bonding arrangement. Furthermore, the measured density of mod. I° is lower than the density of mod. II and thus both, the IR- and the density-rule are violated in this polymorphic system.

Structural characteristics and crystal polymorphism of three local anaesthetic bases: Crystal polymorphism of local anaesthetic drugs: Part VII

Benzocaine (BZC), butambene (BTN) and isobutambene (BTI) are basic local anaesthetic agents of the ester type, preferentially used for surgery and dental procedures. The compounds, official in the USP (BZC and BTN) and Ph. Eur. (BZC), were each found to exist in two polymorphic crystal forms and their solid state characteristics have been determined by thermomicroscopy, differential scanning calorimetry (DSC), FTIR-, FT-Raman-spectroscopy as well as X-ray powder diffractometry. This work further emphasizes the comparison of solid state characteristics of three compounds with closely related structural features on molecular level, leading to opportunities for the investigation of structure-property relationships. Mod. I 0 is the particular thermodynamically stable form at room temperature in all of the three systems. This form is present in commercial products and can be crystallized from solvents at room conditions. Mod. II can be obtained by annealing the supercooled melt or fast cooling of a saturated solution, respectively. The endothermic transformation of mod. II to mod. I 0 upon heating confirms that mod. I 0 is thermodynamically stable at ambient conditions (heat of transition rule) whereas mod. II is enantiotropically related to mod. I 0, i.e. is metastable at temperatures above the transition temperature. The metastable forms show different kinetic stabilities at room temperature.

Thermal and X‐ray analysis of polymorphic crystals, melting, and crystalline transformation in poly(butylene adipate)

AbstractPolymorphic crystals and complex multiple melting behavior in an aliphatic biodegradable polyester, poly(butylene adipate) (PBA), were thoroughly examined by wide‐angle X‐ray diffraction (WAXD) and differential scanning calorimetry (DSC). Further clarification on mechanisms of multiple melting peaks related to polymorphic crystal forms in PBA was attempted. More stable α‐form crystal is normally favored for crystallization from melt at higher temperatures (31–35 °C), or upon slow cooling from the melt; while the β‐form is the favored species for crystallization at low temperatures (25–28 °C). We further proved that PBA crystallization could also result in all α‐form even at low temperatures (25–28 °C) if it crystallized with the presence of prior α‐form nuclei. PBA packed with both crystal forms could display as many as four melting peaks (P1 ˜ P4, in ascending temperature order). However, PBA initially containing only the α‐crystal exhibited dual melting peaks of P1 and P3, which are attributed to dual lamellar distributions of the α‐crystal. By contrast, PBA initially containing only the β‐crystal could also exhibit dual melting peaks (P2 and P4) upon scanning. While P2 is clearly associated with melting of the initial β‐crystal, the fourth melting peak (P4), appearing rather broad, was determined to be associated with superimposed thermal events of crystal transformation from β‐ to α‐crystal and final re‐melting of the new re‐organized α‐crystal. Crystal transformation from one to the other or vice versa, lamellae thickening, annealing at molten state, and influence on crystal polymorphism in PBA were analyzed. Relationships and mechanisms of dual peaks for isolate α‐ or β‐crystals in PBA are discussed. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 1662–1672, 2005

Physico-chemical characterization of an active pharmaceutical ingredient

The physico-chemical properties and polymorphism of a new active pharmaceutical ingredient entity has been analyzed and the gain of knowledge during the chemical development of the substance is described. Initial crystallization revealed an anhydrous crystal form with good crystallinity and a single, sharp DSC melting peak at 171°C and a straightforward development of this crystal form seemed possible. However, during polymorphism screening, new crystalline forms were detected that were often analyzed as mixtures of crystal forms. The process of characterization and identification of the different crystalline forms and its thermodynamical relationship has been supported by a combination of experimental and computational work including determination of the three-dimensional structures of the crystal forms. The crystal structure of one polymorphic form was solved by single crystal X-ray structure analysis. Unfortunately, Mod B resisted in formation of suitable single crystals, but its structure could be solved by high resolution powder diffraction data analysis using synchrotron radiation. Calculation of the theoretical X-ray powder diffraction pattern from three dimensional crystal coordinates allowed an unambiguous identification of the different crystalline forms. Two polymorphic crystal forms of the API-CG3, named Mod A and Mod B, are enantiotropic whereas Mod B is the most stable polymorph at room temperature up to about 50°C and Mod A at temperatures above 50°C. The mechanism of the solid-solid transition can be explained by analyzing the molecular packing information gained from the single crystal structures. A third crystalline form with the highest melting peak turned out to be not a polymorphic or pseudopolymorphic crystal modification of our API-CG3 but a chemically different substance.

Switching between kinetic and thermodynamic control: calcium carbonate growth in the presence of a simple alcohol

Calcium carbonate was grown by diffusion of gaseous carbon dioxide into aqueous calcium chloride–alcohol solutions and the relationship between the alcohol additive and the growing crystal was investigated. There was no evidence that crystal growth was controlled through any specific molecular interaction between the growing calcium carbonate facets and the alcohol. Under control conditions, both calcite and vaterite were grown in a ratio of 1∶3, respectively. However, the overall trend for all the alcohols investigated was preferential precipitation of calcite, as compared to the control. In addition to this primary alcohol effect, a morphological variant of perfect calcitic rhombohedra, a hopper crystal, was observed. This morphological form was present in all growth solutions, but made up an increasing proportion of the calcite fraction for solutions with viscosities above approximately 1.6 mPa s, irrespective of the absolute alcohol concentration. The different morphological and polymorphic forms of the calcium carbonate crystals were examined by scanning electron microscopy and powder X-ray diffraction, respectively.

Advanced Raman Spectroscopy for Pharmaceutical and Biological Applications

With the advent of easy to use analytical and research instrumentation the Raman technique has finally become accepted and is now widely used by pharmaceutical and biomedical companies. Applications range from simple polymorphic crystal form and protein studies to Raman mapping studies of active/excipient distribution and association that give a better understanding of drug dissolution and effectiveness. Examples of such work will be discussed.More recently with the growing confidence in the power of Raman spectroscopy pharmaceutical and biomedical companies have teamed with instrument companies to develop specific Raman tools. One example of this is the development of a Raman mutiwell/microarray analyzer. High Throughput screening (HTS) is the latest approach in analytical technology. Used particularly in the pharmaceutical industry and in the life science laboratories, this method enables systematic screening of drug design and high throughput analysis of batch production. Combinatorial chemistry is a statistical approach in synthetic chemistry.

Polymorphism of milk fat studied by differential scanning calorimetry and real‐time X‐ray powder diffraction

AbstractThe crystallization behavior of milk fat was investigated by varying the cooling rate and by isothermal solidification at various temperatures while monitoring the formation of crystals by differential scanning calorimetry (DSC) and X‐ray powder diffraction (XRD). Three different polymorphic crystal forms were observed in milk fat: γ, α, and β′. The β‐form, occasionally observed in previous studies, was not found. The kind of polymorph formed during crystallization of milk fat from its melted state was dependent on the cooling rate and the final temperature. Moreover, transitions between the different polymorphic forms were shown to occur upon storing or heating the milk fat. The characteristic DSC heating curve of milk fat is interpreted on the basis of the XRD measurements, and appears to be a combined effect of selective crystallization of triglycerides and polymorphism.

Protective colloids and polylactic acid co-affecting the polymorphic crystal forms and crystallinity of indomethacin encapsulated in microspheres

The co-effect of protective colloids and polylactic acid (PLA) on the polymorphic crystal forms and crystallinity of indomethacin (IMC) in IMC-loaded PLA microspheres was investigated with differential scanning calorimetry, infrared spectroscopy and x-ray diffractometry, to evaluate the polymorphic crystal forms and crystallinity of IMC encapsulated in PLA microspheres. The surfactant, sodium dodecylsulphate (SDS), was alsoused as adispersing agent. The results indicate that the polymorphism and crystallinity of IMC encapsulated in IMC-loaded PLA microspheres was dependent on the type of protective colloid and PLA used. The amorphous state and alpha-form of IMC were found in the IMC-loaded PLA microspheres prepared using polysaccharide (pectin or beta-cyclodextrin) as a protective colloid or SDS as a dispersing agent. However, theamorphous andmethylenechloride solvate of IMC seemed to exist in the IMC-loaded PLA microspheres prepared with the proteins (gelatin or albumin), synthetic cellulose derivative (methyl cellulose or hydroxylpropyl methylcellulose) or the synthetic nonionic polymer (polyvinyl alcohol, polyvinyl pyrrolidone or biosoluble polymer) as a protective colloid. PLA was found to express a certain crystallinity in microspheres and not be affected by the protective colloids, but it played a more important role in influencing the crystallization of IMC during microencapsulation than the protective colloids. No interaction occurred in the physical mixture of IMC and PLA, nor in the IMC-loaded PLA microspheres.

Polymorphic crystal forms and morphology of syndiotactic polystyrene in miscible states

X-ray diffraction and optical microscopy characterization were performed to evaluate the phenomenon of alteration of polymorphism of syndiotactic polystyrene (s-PS) in the presence of other blending miscible polymers: poly(2,6-dimethyl-p-phenylene oxide) (PPO) or atactic polystyrene (a-PS). Both α and β crystal forms were observed in the neat s-PS sample, but only β-form crystal was found in miscible blends of s-PS with a-PS or PPO. The order and neighboring chain segments of neat s-PS are different from those of s-PS/PPO or s-PS/a-PS blends; thus, it is plausible that the greater randomness in the melt state of s-PS/a-PS or s-PS/PPO blends might be unfavorable for formation of α-form crystals from melts. The final spherulitic morphology the s-PS/a-PS or s-PS/PPO blends suggests that the amorphous-state miscibility of does not change much the spherulitic structure of s-PS. The radial growth rate is, in general, depressed with the presence of blending miscible polymers in s-PS of equal Tg or PPO of higher Tg. © 1998 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 36: 2725–2735, 1998

Structural study of α-amino-acid crystals by 1H CRAMPS NMR spectroscopy

1 H CRAMPS (combined rotation and multiple pulse spectroscopy) NMR was applied to structural analysis of polymorphic forms of α-amino acid crystals in order to test the power of 1 H CRAMPS NMR compared with the 13 C and 15 N NMR methods. We have studied two different stages of α-amino acid crystals: α-glycine and γ-glycine, and A-histidine and B-histidine. As a result, it was found that the α-methylene proton (H α) signal of α-glycine splits into two peaks (4.4 and 3.4 ppm), but that of γ-glycine gives a singlet peak (3.3 ppm), which was reasonably explained by the 1 H electrostatic potential charge calculation for this glycine system. Furthermore, it was found that the 1 H chemical shift difference between the H 2 and H 5 peaks from the imidazole ring of A-histidine (0.4 ppm) could easily be distinguished from that of B-histidine (0.9 ppm). Thus, the 1 H chemical shifts of α-amino acids are very sensitive to a slight difference in magnetic surroundings of protons as well as to differences of the hydrogen bond network. Therefore, the 1 H CRAMPS NMR spectra are very useful for the structural analysis of α-amino acid crystals.