Ethyl N-[2-(4-phenoxyphenoxy)ethyl]-carbamate

peer-reviewedThe title compound, C17H19NO4, which is a non-toxic insect growth regulator with the common name fenoxycarb, contains two independent and conformationally different molecules in the asymmetric unit. Although the inter-ring dihedral angles are similar [62.21 (15) and 63.00 (14) ], the side-chain orientations differ. In the crystal, the molecules are linked through N—H O hydrogen-bonding associations, giving chains which extend along [110], while intra- and intermolecular aromatic C—H interactions give sheet structures parallel to [110].PUBLISHEDpeer-reviewe

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.</p

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

Impact of additives on drug particles during liquid antisolvent crystallization and subsequent freeze-drying

The impact of single or combinations of additives on the generation of nanosuspensions of two poorly water-soluble active pharmaceutical ingredients (APIs), fenofibrate (FF) and dalcetrapib (DCP), and their isolation to the dry state via antisolvent (AS) crystallization followed by freeze-drying was explored in this work. Combinations of polymeric and surfactant additives such as poly(vinyl alcohol) or hydroxypropyl methyl cellulose and sodium docusate were required to stabilize nanoparticles (∼200−300 nm) of both APIs in suspension before isolation to dryness. For both FF and DCP, multiple additives generated the narrowest, most stable particle size distribution, with the smallest particles in suspension, compared with using a single additive. An industrially recognized freeze-drying process was used for the isolation of these nanoparticles to dryness. When processed by the liquid AS crystallization followed by freeze-drying in the presence of multiple additives, a purer monomorphic powder for FF resulted than when processed in the absence of any additive or in the presence of a single additive. It was noted that all nanoparticles freeze-dried in the presence of additives had a flat, flaky habit resulting in large surface areas. Agglomeration occurred during freeze-drying, resulting in micron-size particles. However, after freeze-drying, powders produced with single or multiple additives showed similar dissolution profiles, irrespective of aging time before drying, thus attenuating the advantage of multiple additives in terms of size observed before the freeze-drying process.</p

Impact of Additives on Drug Particles during Liquid Antisolvent Crystallization and Subsequent Freeze-Drying

The impact of single or combinations of additives on the generation of nanosuspensions of two poorly water-soluble active pharmaceutical ingredients (APIs), fenofibrate (FF) and dalcetrapib (DCP), and their isolation to the dry state via antisolvent (AS) crystallization followed by freeze-drying was explored in this work. Combinations of polymeric and surfactant additives such as poly­(vinyl alcohol) or hydroxypropyl methyl cellulose and sodium docusate were required to stabilize nanoparticles (∼200–300 nm) of both APIs in suspension before isolation to dryness. For both FF and DCP, multiple additives generated the narrowest, most-stable particle size distribution, with the smallest particles in suspension, compared with using a single additive. An industrially recognized freeze-drying process was used for the isolation of these nanoparticles to dryness. When processed by the liquid AS crystallization followed by freeze-drying in the presence of multiple additives, a purer monomorphic powder for FF resulted than when processed in the absence of any additive or in the presence of a single additive. It was noted that all nanoparticles freeze-dried in the presence of additives had a flat, flaky habit resulting in large surface areas. Agglomeration occurred during freeze-drying, resulting in micron-size particles. However, after freeze-drying, powders produced with single or multiple additives showed similar dissolution profiles, irrespective of aging time before drying, thus attenuating the advantage of multiple additives in terms of size observed before the freeze-drying process

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 degrees C and 50 degrees 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 degrees 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 degrees 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). (c) 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2183-2189, 201

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.</p

Investigation of the particle growth of fenofibrate following antisolvent precipitation and freeze-drying

Submicron to small-micron-sized particles of the hydrophobic drug, fenofibrate, were prepared by controlled crystallization in order to influence its dissolution behavior. An antisolvent precipitation process successfully generated particles (200-300 nm) which matched the size and dissolution behavior of a commercial wet-milled formulation of the drug. Although the preparation of submicron-sized particles was straightforward, retaining their size in suspension and during isolation was a challenge. Additives were employed to temporarily stabilize the suspension, and extend the time window for isolation of the submicron particles. Precipitated particles were isolated primarily by immediate freeze-drying, but drying stresses were found to destabilize the fragile submicron system. The growth pathway of particles in suspension and during oven and freeze-drying were compared. Although the growth pathways appeared considerably different from a visual morphological perspective, an investigation of the electron diffraction patterns and the inner-particle surfaces showed that the growth pathways were the same: molecular addition by Ostwald ripening. The observed differences in the time-resolved particle morphologies were found to be a result of the freeze-drying process

Investigation into solid and solution properties of quinizarin

Polymorphism, crystal shape and solubility of 1,4-dihydroxyanthraquinone (quinizarin) have been investigated in acetic acid, acetone, acetonitrile, n-butanol and toluene. The solubility of FI and FII from 20 degrees C to 45 degrees C has been determined by a gravimetric method. By slow evaporation, pure FI was obtained from n-butanol and toluene, pure FII was obtained from acetone, while either a mixture of the two forms or pure FI was obtained from acetic acid and acetonitrile. Slurry conversion experiments have established an enantiotropic relationship between the two polymorphs and that the commercially available FI is actually a metastable polymorph of quinizarin under ambient conditions. However, in the absence of FII, FI is kinetically stable for many days over the temperature range and in the solvents investigated. FI and FII have been characterized by infrared spectroscopy (IR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), transmission and ordinary powder X-ray diffraction (PXRD) at different temperatures. The crystal structure of FII has been determined by single-crystal XRD. DSC and high-temperature PXRD have shown that both FI and FII will transform into a not previously reported hightemperature form (FIII) around 185 degrees C before this form melts at 200-202 degrees C. By indexing FIII PXRD data, a triclinic P (1) over bar cell was assigned to FIII. The solubility of quinizarin FI and FII in the pure organic solvents used in the present work is below 2.5% by weight and decreases in the order: toluene, acetone, acetic acid, acetonitrile and n-butanol. The crystal shapes obtained in different solvents range from thin rods to flat plates or very flat leaves, with no clear principal difference observed between FI and FII