Multivariate Analysis of Solubility Parameters for Drug-Polymer Miscibility Assessment in Preparing Raloxifene Hydrochloride Amorphous Solid Dispersions.

The success of obtaining solid dispersions for solubility improvement invariably depends on the miscibility of the drug and polymeric carriers. This study aimed to categorize and select polymeric carriers via the classical group contribution method using the multivariate analysis of the calculated solubility parameter of RX-HCl. The total, partial, and derivate parameters for RX-HCl were calculated. The data were compared with the results of excipients (N = 36), and a hierarchical clustering analysis was further performed. Solid dispersions of selected polymers in different drug loads were produced using solvent casting and characterized via X-ray diffraction, infrared spectroscopy and scanning electron microscopy. RX-HCl presented a Hansen solubility parameter (HSP) of 23.52 MPa1/2. The exploratory analysis of HSP and relative energy difference (RED) elicited a classification for miscible (n = 11), partially miscible (n = 15), and immiscible (n = 10) combinations. The experimental validation followed by a principal component regression exhibited a significant correlation between the crystallinity reduction and calculated parameters, whereas the spectroscopic evaluation highlighted the hydrogen-bonding contribution towards amorphization. The systematic approach presented a high discrimination ability, contributing to optimal excipient selection for the obtention of solid solutions of RX-HCl.

Evaluation of Printability of PVA-Based Tablets from Powder and Assessment of Critical Rheological Parameters.

Fused deposition modeling (FDM) is a rather new technology in the production of personalized dosage forms. The melting and printing of polymer-active pharmaceutical ingredient (API)-mixtures can be used to produce oral dosage forms with different dosage as well as release behavior. This process is utilized to increase the bioavailability of pharmaceutically relevant active ingredients that are poorly soluble in physiological medium by transforming them into solid amorphous dispersions (ASD). The release from such ASDs is expected to be faster and higher compared to the raw materials and thus enhance bioavailability. Printing directly from powder while forming ASDs from loperamide in Polyvinylalcohol was realized. Different techniques such as a change in infill and the incorporation of sorbitol as a plastisizer to change release patterns as well as a non-destructive way for the determination of API distribution were shown. By measuring the melt viscosities of the mixtures printed, a rheological model for the printer used is proposed.

Direct Tableting on a Continuous Manufacturing Line-Impact of Mixing Parameters, Material Densities, and Drug Load on Subsequent Process Parameters and Tablet Quality.

The continuous manufacturing (CM) of solid oral dosage forms has received increased attention in recent years and has become a leading technology in the pharmaceutical industry. A model has been developed based on process data from two design of experiments (DoEs), where the impact of the mixer process parameters, throughput (THR), hold up mass (HUM), impeller speed (IMP), and the input raw material bulk density (BDi), on the continuous process and the resulting drug product has been investigated. These statistical models revealed equations, describing process parameter interactions for optimization purposes. For the exit valve opening width (EV) at the bottom of the continuous mixer (CMT), the combination of high throughput (30 kg/h) and low impeller speed (300 rpm) resulted in optimal process conditions. Apparent bulk density of the blend (BD) within the process, fill depth (FD), and tensile strength (TS) were mainly impacted by input bulk density (BDi) of the tableting mixture, emphasizing the role of material attributes on the continuous manufacturing process. The apparent bulk density itself was, other than from the input bulk density, equally dependent from THR and IMP in opposite deflections. However, process parameters (THR and IMP) revealed a minor impact on the apparent BD compared to the input bulk density. FD was impacted mainly by THR ahead of IMP and the TS by IMP and THR to a similar extend, in opposite deflections. A simplified linear model to estimate the input bulk density revealed satisfactory prediction quality when included in the derived statistical model equations.

Bioanalytical Workflow for Qualitative and Quantitative Assessment of Hot-Melt Extruded Lysozyme Formulations.

Structural and functional integrities of formulated proteins are key characteristics that provide a better understanding of influencing factors and their adjustment during formulation development. Here, the procedures commonly used for protein analysis were applied and optimized to obtain a higher degree of accuracy, reproducibility, and reliability for the analysis of lysozyme extracts from hot-melt extrudates (HME). The extrudates were prepared with polyethylene glycol 20 000. The test lysozyme HMEs were subjected to extraction procedures and analytical methods following the International Council of Harmonization guidelines for testing the active protein ingredient Q 1 A (R2) in its pure and formulated form. Therefore, reversed-phase high-pressure liquid chromatography, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, matrix-assisted laser desorption ionization mass spectrometry, and fluorescence-based activity measurements were applied to study lysozyme stability and function after formulation. Long-term accelerated stability studies were performed for the pure and formulated protein. Our findings revealed a high degree of stability for lysozyme toward different temperatures and storage times, confirming that HME is a suitable formulation alternative that preserves lysozyme's properties and stability. The presented methods and workflow are recommended to be exploited for further protein drugs to assess usability and compatibility concerning different pharmaceutical applications.

Assessment of Abrasion-Induced Visual Defects in Twin Screw Wet Granulation Using Wall Friction Measurements.

Starting point of the presented study were abrasion effects occurring during a twin screw wet granulation (TSG) process of a new chemical entity (NCE) formulation, resulting in gray spots on the final tablets. Several actions and systematic changes of equipment and process parameter settings of TSG process were conducted which reduced the visual defect rate of the tablets, i.e., gray spots on the surface, below the specification limit. To understand the rationale and mechanism behind these improvements, correlations of defect rates and wall friction measurements using a Schulze ring shear tester were evaluated. To check the suitability of the method, a broad range of wall materials as well as powder formulations at various moisture levels were investigated with regard to their wall friction angle. As differences in wall friction angle could be detected, further experiments were conducted using wall material samples made out of different screw materials for TSG. Evaluation of these screw wall material samples gave first hints, which screw materials should be preferred in regard of friction for TSG process. In the finally presented case study, wall friction measurements were performed using the above mentioned NCE formulation with known abrasion issues at TSG processing. The results confirmed that changes which led to a reduced visual defect rate of tablets correlated with a decreased wall friction angle. The results suggest wall friction measurements as a potent tool for equipment selection and establishment of a suitable process window prior to conducting TSG experiments.

In vitro and in vivo assessment of hydroxypropyl cellulose as functional additive for enabling formulations containing itraconazole.

Using polymers as additives to formulate ternary amorphous solid dispersions (ASDs) has successfully been established to increase the bioavailability of poorly soluble drugs, when one polymer is not able to provide both, stabilizing the drug in the matrix and the supersaturated solution. Therefore, we investigated the influence of low-viscosity hydroxypropyl cellulose (HPC) polymers as an additive in HPMC based ternary ASD formulations made by hot-melt extrusion (HME) on the bioavailability of itraconazole (ITZ). The partitioning potential of the different HPC grades was screened in biphasic supersaturation assays. Solid-state analytics were performed using differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD). The addition of HPCs, especially HPC-UL, resulted in a superior partitioned amount of ITZ in biphasic supersaturation assays. Moreover, the approach in using HPCs as an additive in HPMC based ASDs led to an increase in partitioned ITZ compared to Sporanox® in biorelevant biphasic dissolution studies. The results from the biphasic dissolution experiments correlated well with the in vivo studies, which revealed the highest oral bioavailability for the ternary ASD comprising HPC-UL and HPMC.

From benchtop to pilot scale-experimental study and computational assessment of a hot-melt extrusion scale-up of a solid dispersion of dipyridamole and copovidone.

The aim of our work was to study and define a computationally-based adiabatic scale-up methodology for a hot-melt extrusion (HME) process to produce an amorphous solid dispersion (ASD). As a drug product becomes commercially viable, there is a need for scaling up the manufacturing process. In the case of HME used for the formation of ASDs, scale-up can be challenging due to the fundamental differences in how heat is generated in extruders of differing scale, i.e. conduction vs. viscous dissipation and the significant role heat generation plays in determining the final product attributes. Using a 30%w/w dipyridamole-in-copovidone formulation, 11 mm-, 16 mm- and 24 mm-diameter extruders with L/D 40, solid-state characterization tools, a geometric scaling equation, and Ludovic® twin-screw extrusion software, we compared the total imparted material energy, the conducted energy and the difference between barrel and melt temperature at die exit for various feed rates and screw speeds. Numerical simulation identified desirable adiabatic conditions at multiple extruder scales in agreement with the chosen scaling factor. With the use of computational tools, the energetics in an extrusion process can be evaluated and processing conditions can be selected to identify the most efficient scaling of a HME process.

Teamwork in Trauma: System Adjustment to a Protocol for the Management of Multiply Injured Patients.

OBJECTIVES: We developed a protocol to determine the timing of definitive fracture care based on the adequacy of resuscitation. Inception of this project required a multidisciplinary group, including physicians from anesthesiology, general trauma and critical care, neurosurgery, orthopaedic spine, and orthopaedic trauma. The purposes of this study were to review our initial experience with adherence to protocol recommendations and to assess barriers to implementation. DESIGN: Prospective. SETTING: Level 1 trauma center. INTERVENTION: Definitive fixation of pelvis, acetabulum, spine, and femur fractures within 36 hours of injury, based on laboratory parameters for acidosis. MAIN OUTCOME MEASUREMENTS: Three hundred five consecutive skeletally mature patients with Injury Severity Score ≥ 16 (mean, 26.4) and 346 fractures of the proximal or diaphyseal femur (n = 152), pelvic ring (n = 56), acetabulum (n = 44), and/or spine (n = 94) were treated surgically. Adherence to the protocol was defined as definitive fixation within 36 hours of injury in resuscitated patients. All patients were adequately resuscitated within that time. Patient demographic and injury characteristics, date and time of presentation, and reasons for delay were recorded. RESULTS: Two hundred fifty-one patients (82%) with 287 fractures were treated according to the protocol, whereas 54 patients (18%) with 59 fractures were definitively stabilized on a delayed basis (mean, 90 hours). Delay was not related to patient age, Injury Severity Score, day of week, or time of presentation. Before implementation of this protocol, 76% were treated on a delayed basis, demonstrating improvement for each fracture type: spine (79% of previous patients with delay), pelvis (57%), acetabulum (72%), and femur (22%); all P < 0.0001 for more frequently delayed surgery before the protocol. Surgeon choice to delay the procedure accounted for 67% of reasons for delay. Other reasons included intensivist choice (13%), operating room availability (7.4%), patient choice (3.7%), severe head injury (5.6%), or cardiac issues (3.7%). Our trauma center and surgeons became more accustomed to the protocol and had fewer delays over time; 10% were delayed 2 years after implementation. CONCLUSIONS: Management of trauma patients with injury to multiple systems requires teamwork among providers from related specialties and hospital support, in terms of operating room access, with appropriate ancillary personnel and equipment. Our system adjusted quickly to the protocol. Surgeon preference was the most common reason for delayed fixation, but within 24 months, only 10% of fractures were treated on a delayed basis, as long as patients were resuscitated.