Andrew Otte

Assessment of Milling-Induced Disorder of Two Pharmaceutical Compounds

The goal of this study was to provide a better framework for understanding the bulk and surface disorder in milled crystalline materials. The surface and bulk properties of two model compounds, ketoconazole and griseofulvin, were characterized by inverse gas chromatography as a function of cryomilling time. Cryomilling was used to decrease the effect of temperature-induced changes, which commonly occur during milling. A reduction in crystallinity was observed for both compounds by powder X-ray diffraction and differential scanning calorimetry (DSC). Particle size analysis revealed a continued mode of attrition for griseofulvin, whereas attrition followed by growth was observed for ketoconazole. An increase in surface energy for both compounds was noticed upon initial milling, followed by a decrease as milling time continued. A determination and comparison of the surface phase transformations using chromatographic methods and DSC was carried out. Both ketoconazole and griseofulvin showed an earlier phase transformation relative to DSC. It is proposed that an intermediate metastable state for griseofulvin and a change in the surface structure of ketoconazole is the consequence of the cryomilling process.

Matrix‐Assisted Cocrystallization (MAC) Simultaneous Production and Formulation of Pharmaceutical Cocrystals by Hot‐Melt Extrusion

A novel method for the simultaneous production and formulation of pharmaceutical cocrystals, matrix-assisted cocrystallization (MAC), is presented. Hot-melt extrusion (HME) is used to create cocrystals by coprocessing the drug and coformer in the presence of a matrix material. Carbamazepine (CBZ), nicotinamide (NCT), and Soluplus were used as a model drug, coformer, and matrix, respectively. The MAC product containing 80:20 (w/w) cocrystal:matrix was characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffraction. A partial least squares (PLS) regression model was developed for quantifying the efficiency of cocrystal formation. The MAC product was estimated to be 78% (w/w) cocrystal (theoretical 80%), with approximately 0.3% mixture of free (unreacted) CBZ and NCT, and 21.6% Soluplus (theoretical 20%) with the PLS model. A physical mixture (PM) of a reference cocrystal (RCC), prepared by precipitation from solution, and Soluplus resulted in faster dissolution relative to the pure RCC. However, the MAC product with the exact same composition resulted in considerably faster dissolution and higher maximum concentration (∼five-fold) than those of the PM. The MAC product consists of high-quality cocrystals embedded in a matrix. The processing aspect of MAC plays a major role on the faster dissolution observed. The MAC approach offers a scalable process, suitable for the continuous manufacturing and formulation of pharmaceutical cocrystals.

Milling induces disorder in crystalline griseofulvin and order in its amorphous counterpart

This study investigates two apparently similar thermal signatures, shaped as bimodal exotherms, observed when either the crystalline or the amorphous from of the drug are subjected to milling. Crystalline griseofulvin was cryomilled and the (quenched-melt) amorphous form was subjected to either cryomilling or grinding. The thermal and surface properties of the resulting samples were analyzed using differential scanning calorimetry (DSC) and surface energy analysis. After milling, both the crystalline and the amorphous material revealed visually similar bimodal exothermic events when the heating rate was 20 °C min−1. Under different heating rates, the pair of DSC peaks for the bimodal exotherm of each material behaved entirely different from each other. The two peaks of the bimodal event, as well as the glass transition, can be kinetically resolved for the ground amorphous form using standard mode DSC. In contrast, similar analysis was unable to resolve the bimodal exotherm or a glass transition in the case of the cryomilled crystals. Furthermore, cryomilled crystals do not exhibit a glass transition even when analyzed using modulated DSC. Synchrotron sourced X-ray analysis revealed that grinding the amorphous material results in the nucleation and growth of the crystalline form. Milling thus induces disorder in the crystals of griseofulvin but induces order in the amorphous form of the drug. The surface of the two milled systems consistently exhibited different energetics under a wide range of relative humidity conditions. These findings suggest that cryomilling induces both bulk and surface disorder, specifically, a certain level of dislocations on the crystal. In contrast, grinding the amorphous material lowers the activation energy for crystal formation, inducing nuclei formation and growth throughout the amorphous matrix.

Formulation and characterization of a liquid crystalline hexagonal mesophase region of phosphatidylcholine, sorbitan monooleate, and tocopherol acetate for sustained delivery of leuprolide acetate

Although liquid crystal (LC) systems have been studied before, their utility in drug delivery applications has not been explored in depth. This study examined the development of a 1-month sustained release formulation of leuprolide acetate using an in situ-forming LC matrix. The phase progression upon water absorption was tested through construction of ternary phase diagrams of phosphatidylcholine, sorbitan monooleate, and tocopherol acetate (TA) at increasing water content. Small angle X-ray scattering revealed the presence of lamellar and hexagonal mesophases. The physicochemical characteristics and in vitro drug release were evaluated as a function of the ternary component ratio and its resultant phase behavior. Formulations with increased water uptake capacity displayed greater drug release and enhanced erodability. Removal of TA resulted in increased water uptake capacity and drug release, where 8% (w/w) TA was determined as the critical concentration threshold for divergence of release profiles. In conclusion, characterization of the resultant HII mesophase region provided information of the impact the individual components have on the physicochemical properties and potential drug release mechanisms. This high mitigating impact of TA on drug release indicates the use of TA as a tailoring agent, broadening the therapeutic applications of this LC system.

Physicomechanical and antibacterial properties of experimental resin‐based dental sealants modified with nylon‐6 and chitosan nanofibers

This study aimed to develop and evaluate resin-based experimental dental sealants containing electrospun nylon-6 (N6) and chitosan (CH) fibers in an attempt to improve the physicomechanical properties and provide an antibacterial protective effect, respectively. Electrospun N6 and CH mats were immersed into a resin mixture, light-cured, and then cryomilled to obtain micron-sized resin-modified fiber particles. Different levels of the novel cryomilled particles (i.e. 1, 2.5, and 5% relative to the resin mixture, % by weight) were used to prepare the N6- and CH-containing sealants. A commercial sealant and the experimental resin mixture (unfilled) were used as controls. Flexural strength (FS), Vickers microhardness (VH), and agar diffusion tests were performed. The data were analyzed at the 5% significance level. No significant difference in fiber diameter of N6 (503 ± 31 nm) and CH (595 ± 38 nm) was observed. Upon cryomilling, the resin-modified CH and N6 mats led to the formation of irregularly-shaped particles, with an average diameter of 14.24 µm and 15.87 µm, respectively. CH-5% had significantly higher FS (115.3 ± 1.3 MPa) than all the other groups. CH-1% had significantly higher hardness values (38.3 ± 0.3 VHN) than all the other groups. Collectively, the results indicated that CH-containing sealants presented the highest FS and hardness; however, none of the CH-containing sealants displayed antimicrobial properties.

Investigation of Film with β-Galactosidase Designed for Stabilization and Handling in Dry Configuration

Gelatin-based films with an immobilized enzyme designed for extending the stability of the protein in dry, non-powder configuration with precise dosing attributes were subjected to stress conditions of temperature and relative humidity. β-galactosidase was used as model functional protein. The film configuration preserved the activity of the enzyme under the different storage conditions investigated, which include room temperature under low (ambient) and high (75%) relative humidity, and 36 °C under low (oven) and high relative humidity conditions for a period of 46 days. The influence of the enzyme and plasticizer (glycerol) on the physical and mechanical properties of the films was investigated using DMA (dynamic mechanical analysis). Films containing 5% β-galactosisdase and glycerol concentrations of 14% or greater exhibited greater tensile strength, Young’s modulus, and elongation at break than films with equal concentrations of plasticizer but devoid of any enzyme. The surface texture of the films was analyzed using scanning electron microscopy (SEM). β-galactosidase and glycerol have opposite effects on the surface morphology of the films. Increasing concentrations of the enzyme result in rougher film surface, whereas increasing the concentration of glycerol leads to films with denser and smoother surface. The results obtained suggest that the dry film configuration approach can help in facilitating the stabilization, handling, storage, and transportation of functional proteins in a cost effective manner.

Liquid crystalline drug delivery vehicles for oral and IV/subcutaneous administration of poorly soluble (and soluble) drugs

Poorly soluble drug molecules often have low bioavailability issues and absorption problems in the clinical setting. As the number of poorly soluble drugs increases from discovery, developing technologies to enhance their solubility, while also controlling their release is one of the many challenges facing the pharmaceutical industry today. Liquid crystalline systems, nanoparticulate or macro-matrix, self-assemble in the presence of an aqueous environment and can provide a solubility enhancement, while also controlling the drug release rate. This review examines the fundamentals of liquid crystalline systems through the representative literature, concluding with examples of liquid crystalline systems in clinical trials development. The review focus is on the potential of utilizing liquid crystalline systems for poorly soluble drugs, in the areas of oral delivery and IV/subcutaneous, followed by water soluble molecules. Key considerations in utilizing liquid crystalline systems advantages while also discussing potential areas of key research that may be needed will be highlighted.

The in vivo transformation and pharmacokinetic properties of a liquid crystalline drug delivery system

A liquid crystalline (LC) system, composed of phosphatidylcholine, sorbitan monoleate, and tocopherol acetate, was investigated to understand the in vivo transformation after subcutaneous injection, coupled with the physicochemical and pharmacokinetic properties of the formulation. The rat model was utilized to monitor a pseudo-time course transformation from a precursor LC formulation to the LC matrix, coupled with the blood concentration profiles of the formulations containing leuprolide acetate. Three formulations that result in the HII phase, demonstrating dissimilar in vitro release profiles, were used. The formulation showing the highest AUC, Cmax and Tmax, also displayed the greatest release rate in vitro, the lowest viscosity (LC matrix), and an earlier transformation (LC precursor to matrix) in vivo. A potential link between viscosity, phase transformation, and drug release properties of a liquid crystalline system is described.