Preparation and formulation of progesterone para-aminobenzoic acid co-crystals with improved dissolution and stability.

The crystal structure of a new Progesterone (PROG) co-crystal with para-aminobenzoic acid (PABA) showing enhanced solution properties is reported. PROG-PABA co-crystal was first identified though an in silico coformer screening process using the CSD Co-crystal deign function, then confirmed through a solution evaporation crystallisation experiment. The resulting co-crystal was characterized using single crystal X-ray diffraction, differential scanning calorimetry and Fourier-transform infrared spectroscopy. Liquid assisted grinding was selected as a suitable scale up method compared to spray drying and antisolvent methods due to minimal starting material phases in the final product. Following scale up, aqueous solubility, stability and dissolution measurements were carried out. PROG-PABA showed increased distinct aqueous solubility and dissolution compared to PROG starting material and was shown to be stable at 75 % relative humidity for 3 months. Tablets containing co-crystal were produced then compared to the Utrogestan® soft gel capsule formulation through a dissolution experiment. PROG-PABA tablets showed a substantial increase in dissolution over the course of the experiment with over 30× the amount of PROG dissolved at the 3-hour time point. This co-crystal shows positive implications for developing an improved oral PROG formulation.

Spray dried progesterone formulations for carrier free dry powder inhalation.

Low oral absorption and extensive first pass metabolism of progesterone is reported for many oral formulations which warrants investigation into other routes of administration. It is the aim of this study to investigate the generation of inhaled formulations of progesterone though a spray drying approach with a focus on how spray drying impacts the physicochemical properties of progesterone. Formulations of progesterone with L-leucine and hydroxypropyl methylcellulose acetate succinate (HPMCAS) are reported to this aim. X-ray diffraction, spectroscopy and thermal analysis were used to characterise these formulations and confirmed that progesterone crystallises as the Form II polymorph during spray drying regardless of the solvent used. The resultant formulations showed higher aqueous solubility than progesterone Form I starting material and the addition of HPMCAS was shown to temporarily enable a supersaturated state. Thermal analysis was used to show that the Form II polymorph was sensitive to transformation to Form I during heating. The addition of L-leucine to the formulations reduced the temperature for the polymorphic transformation by âˆ¼ 10 °C. However, when HPMCAS was added to the formulation, the Form II polymorph was prevented from transforming to the Form I polymorph. Cascade impaction was used to determine the aerosol performance of the spray dried powders and showed promising lung deposition profiles (mass median aerodynamic diameter 5 µm) with significant variation depending on the organic solvent used and the ratio of organic to aqueous phase in the feedstock. However, further optimisation of formulations was required to direct more progesterone into the alveolar regions. The addition of HPMCAS was seen to increase the alveolar deposition and therefore formed a formulation with a lower fine particle fraction and mass median aerodynamic diameter. The most suitable formulation for inhalation was formed from a 50:50 acetone:water mixture and showed an ED, FPF and FPD of 81.7%, 44.5% and 7.3 mg respectively. Therefore, HPMCAS is suggested as a suitable excipient to increase solubility, prevent polymorphic transformation and improve inhalation properties of spray dried progesterone formulations. This study highlights the use of spray drying to form inhalable progesterone powders with higher solubility which may broaden the application of this medicine.

Preparation and Physiochemical Analysis of Novel Ciprofloxacin / Dicarboxylic Acid Salts.

The crystal structures of four novel dicarboxylic acid salts of ciprofloxacin (CFX) with modified physicochemical properties, prepared by mechanochemical synthesis and solvent crystallization, are reported. A series of dicarboxylic acids of increasing molecular weight was chosen, predicted to interact via a carboxylic acid:secondary amine synthon. These were succinic (SA), glutaric (GA), adipic (AA) and pimelic (PA) acids (4, 5, 6, 7 carbon atoms respectively). Characterized by single crystal and powder X-ray diffraction, Fourier-Transform Infrared Spectroscopy, thermogravimetric analysis, differential scanning calorimetry, scanning electron microscopy and aqueous solubility measurements, these salts showed distinct physicochemical properties relative to ciprofloxacin base. Searches of the Cambridge Structural Database (CSD) confirmed CFX-SA, CFX-GA, CFX-AA and CFX-PA to be novel crystal structures. Furthermore, the GA salt has substantially higher solubility than the widely available hydrochloride monohydrate salt (CFX-HCl·H2O). CFX-SA, CFX-GA and CFX-AA showed minimum inhibitory concentration (MIC) of 0.008 g/L and CFX-PA showed MIC of 0.004 g/L. The prepared CFX salts retained antibacterial activity exhibiting equivalent antimicrobial activity to CFX-HCl·H2O. These salts have positive implications for increasing the application of CFX beyond conventional oral formulations and highlight mechanochemical activation as suitable production method.

Antifungal nanosuspensions with surfactants and silver for the treatment of onychomycosis.

Fungal nail infection (Onychomycosis) often requires prolonged treatment and is associated with a high risk of resistance to treatment. Here in this contribution, we introduce a novel approach to enhance penetration and antifungal activity of the antifungal drug griseofulvin (GF). Solid dispersions were prepared with hydroxypropyl methylcellulose acetate succinate (HPMCAS) and combined with surfactant (either sodium dodecyl sulphate (SDS), dodecyl trimethylammonium bromide (DTAB), or Pluronic F127) using mechanochemical activation. The prepared powders were then suspended with spray-dried silica-coated silver nanoparticles and applied onto infected bovine hooves to assess permeability and antifungal activity. The results showed that the prepared nanosuspensions significantly suppressed fungal activity causing disruption of fungal biofilms. Raman mapping showed enhanced permeation while dynamic vapor sorption (DVS), and particle size measurements showed varied effects depending on the type of surfactant and milling conditions. The prepared nanosuspensions displayed enhanced solubility of the poorly soluble drug reaching approximately 1.2 mg/mL. The results showed that the dispersions that contained DTAB displayed maximum efficacy while the inclusion of colloidal silver did not seem to significantly improve the antifungal activity compared to other formulations.

Pulmonary Drug Delivery of Antimicrobials and Anticancer Drugs Using Solid Dispersions.

It is well established that currently available inhaled drug formulations are associated with extremely low lung deposition. Currently available technologies alleviate this low deposition problem via mixing the drug with inert larger particles, such as lactose monohydrate. Those inert particles are retained in the inhalation device or impacted in the throat and swallowed, allowing the smaller drug particles to continue their journey towards the lungs. While this seems like a practical approach, in some formulations, the ratio between the carrier to drug particles can be as much as 30 to 1. This limitation becomes more critical when treating lung conditions that inherently require large doses of the drug, such as antibiotics and antivirals that treat lung infections and anticancer drugs. The focus of this review article is to review the recent advancements in carrier free technologies that are based on coamorphous solid dispersions and cocrystals that can improve flow properties, and help with delivering larger doses of the drug to the lungs.

A New Species of Lizard Endemic to Sierra de Fiambalá, Northwestern Argentina (Iguania: Liolaemidae: Phymaturus). Integrated Taxonomy Using Morphology and DNA Sequences: Reporting Variation Within the antofagastensis Lineage.

The northernmost distributed group of lizards belonging to Phymaturus occurs in rocky outcrops of the Puna region between 3600-4200 m in Argentina. In a recent phylogenetic study based on morphological and genetic information, the monophyly of this small lineage was corroborated. This group is formed by Phymaturus antofagastensis, P. laurenti, P. denotatus, P. mallimaccii and a population of uncertain taxonomic status until the present study. After obtaining new samples and observations, we described a new species belonging to this lineage that is known only from Sierra de Fiambalá, being the species of Phymaturus living at the highest elevation ever recorded (4500 m). Males have a homogeneous yellow dorsum and lack melanic coloration over their heads, a phenomenon found in males of most species of the palluma group. We provide a detailed diagnosis, including characters from the squamation, coloration and significant differences found among continuous characters (ANOVA). Furthermore, we present genetic distances among members of the mallimaccii subclade based on sequences of the cytb marker. We provide color photos showing pattern variation of males and females. We reanalyze the phylogenetic relationships within the entire palluma group and update info on all members of the antofagastensis lineage based on new samples and make a better supported hypothesis. We also evaluate the phylogenetic position of the new taxon.

But they move! Vicariance and dispersal in southern South America: Using two methods to reconstruct the biogeography of a clade of lizards endemic to South America.

This study aims to identify events that modeled the historical biogeography of Phymaturus, using three methodologies: Spatial Analysis of Vicariance (VIP), Statistical Dispersal-Vicariance Analysis (S-DIVA), and Bayesian Binary Method MCMC (BBM). In order to assign areas for the Dispersal-Vicariance and the BBM analyses, we preferred not to use predefined areas, but to identify areas defined via an endemism analysis of Phymaturus species. The analyses were conducted using the same basic topology, which we obtained by constructing a metatree with two recent phylogenies, both morphology and molecular-based. This topology was also used to obtain time divergence estimates in BEAST, using more outgroups than for the metatree in order to get more accurate estimates. The S-DIVA analysis based on the metatree found 25 vicariance events, 20 dispersals and two extinctions; the S-DIVA analysis based on the BEAST tree yielded 30 vicariance events, 42 dispersal events and five extinctions, and the BBM analysis yielded 63 dispersal events, 28 vicariance events and 1 extinction event. According to the metatree analysis, the ancestral area for Phymaturus covers northern Payunia and southern Central Monte. A vicariant event fragmented the ancestral distribution of the genus, resulting in northern Payunia and southern Central Monte as ancestral area for the P. palluma group, and southern Payunia for the P. patagonicus group. The analysis based on the BEAST tree showed a more complex reconstruction, with several dispersal and extinction events in the ancestral node. The Spatial Analysis of Vicariance identified 41 disjunct sister nodes and removed 10 nodes. The barrier that separates the P. palluma group from the P. patagonicus group is roughly congruent with the southern limit of the P. palluma group. The ancestral range for the genus occupies a central position relative to the distribution of the group, which implies that the species must have migrated to the north (P. palluma group) and to the south (P. patagonicus group). To answer questions related to the specific timing of the events, a molecular clock for Phymaturus was obtained, using a Liolaemus fossil for calibration. The present contribution provides a hypothetical framework for the events that modeled the distribution of Phymaturus.