Effect of magnesium stearate surface coating method on the aerosol performance and permeability of micronized fluticasone propionate.

In this study, we evaluated the aerodynamic performance, dissolution, and permeation behavior of micronized fluticasone propionate (FP) and magnesium stearate (MgSt) binary mixtures. Micronized FP was dry mixed with 2% w/w MgSt using a tumble mixer and a resonant acoustic mixer (RAM) with and without heating. The mixing efficacy was determined by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analysis. Additional techniques were used to determine powder properties such as the dynamic vapor sorption (DVS), particle size distribution (PSD) by laser diffraction light scattering, and particle surface properties by scanning electron microscope (SEM). The aerodynamic performance was studied by the next-generation impactor (NGI) using drug-loaded capsules in a PlastiApi® device. Physiochemical properties such as porosity, particle size distribution, and surface area of the formulations were studied with adsorption and desorption curves fitted to several well-known models including Brunauer-Emmett-Teller (BET), Barret Joyner Halenda (BJH), and the density functional theory (DFT). The dissolution behavior of the formulations collected on the transwell inserts incorporated into stages 3, 5, and 7 of the NGI with a membrane providing an air interface was evaluated. Drug permeability of formulations was assessed by directly depositing particles on Calu-3 cells at the air-liquid interface (ALI). Drug concentration was determined by LC-MS/MS. A better MgSt mixing on micronized FP particles was achieved by mixing with a RAM with and without heating than with a tumble mixer. A significant concomitant increase in the % of emitted dose and powder aerosol performance was observed after MgSt mixing. Formulation 4 (RAM mixing at room temperature) showed the highest rate of permeability and correlation with dissolution profile. The results show that the surface enrichment of hydrophobic MgSt improved aerosolization properties and the dissolution and permeability rate of micronized FP by reducing powder agglomerations. A simple low-shear acoustic dry powder mixing method was found to be efficient and substantially improved the powder aerosolization properties and enhanced dissolution and permeability rate.

Effect of Lipidic Excipients on the Particle Properties and Aerosol Performance of High Drug Load Spray Dried Particles for Inhalation.

High drug load inhalable particles were prepared by co-spray drying a hydrophobic, crystalline, small molecule drug with various lipid or phospholipid excipients at a 9:1 molar ratio to understand the primary drivers of aerosol performance. The effect of excipient structure on solid-state, surface characteristics, and aerodynamic performance of the co-spray dried particles was studied while keeping the spray drying parameters constant. Spray drying of the drug with lipids produced crystalline drug particles, whereas phospholipids produced partially amorphous drug particles. All of the co-spray dried particles were nearly spherical with a smooth surface, except for the spray dried drug particles without excipients - which showed the presence of rough crystals on the surface. All co-spray dried particles showed surface enrichment of the excipient. The surface enrichment of the phospholipids was higher compared to the lipids. Co-spray dried particles that showed higher surface enrichment of excipients showed improved aerosol performance. In comparing all the excipients studied, distearyolphosphatidylcholine (DSPC) showed maximum enrichment on the particle surface and thereby significantly improved aerosol performance. This study demonstrated that the addition of small amounts of lipid excipients during spray drying can change surface morphology, composition, and cohesion, impacting aerosol performance of drugs.

Utilizing Solid-State Techniques and Accelerated Conditions to Understand Particle Size Instability in Inhaled Drug Substances.

Micronization by air jet milling is often used to produce drug substance particles of acceptable respirable size for use in dry powder inhaler formulations. The energy from this process often induces surface disordered sites on the micronized particles with potential consequences for the long-term stability of the drug substance. In this study, two lots of the same drug substance were qualitatively determined to have different extents of disordered surface using dynamic vapor sorption and scanning electron microscopy. These differences led to observable divergences in particle size and morphology between lots of drug substances on long-term and accelerated stability. The studies investigate the contribution of temperature and humidity, morphology prior to milling, and stability behavior post-micronization. The results highlight the importance of controlling the crystallization solvents upstream of micronization and their contribution to a material's susceptibility to milling-induced disorder on long-term physical stability. Furthermore, this work proposes an accelerated technique useful in predicting stability behavior of micronized drug substances in days rather than months, especially in cases where small differences cannot be detected by standard solid-state techniques.

The impact of solid-state form, water content and surface area of magnesium stearate on lubrication efficiency, tabletability, and dissolution.

Magnesium stearate (MgSt) is a widely used pharmaceutical lubricant in tablet manufacturing. However, batch-to-batch variability in hydrate form and surface area can lead to inconsistency in tablet performance. In this work, several unique MgSt samples were studied: traditional monohydrate samples with high surface area, dihydrate forms with high and low surface area, and disordered forms with low and medium water content. The effects of solid-state form and particle properties on lubrication efficiency, tabletability and dissolution were studied for tablets in a model direct compression formulation. It was found that the monohydrate and dihydrate forms had good lubrication efficiency compared to the disordered form, while the disordered form had the best tabletability. The dissolution rate correlated with surface area, where slower dissolution rates corresponded with higher MgSt surface areas. The dihydrate sample with lower surface area had the best performance for this model formulation, in terms of lubrication efficiency, tabletability and dissolution. Overall, it is concluded that the choice of the most appropriate grade of MgSt for a particular formulation depends on a comprehensive evaluation of the impact of MgSt properties on lubrication efficiency, tabletability and dissolution.

Discovery and in Vivo Evaluation of Macrocyclic Mcl-1 Inhibitors Featuring an α-Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere.

Overexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an α-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of 1, a potent Mcl-1 inhibitor (IC50 = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.

Investigation of the absolute bioavailability and human mass balance of navoximod, a novel IDO1 inhibitor.

AIMS: Navoximod (GDC-0919, NLG-919) is a small molecule inhibitor of indoleamine-2,3-dioxygenase 1 (IDO1), developed to treat the acquired immune tolerance associated with cancer. The primary objectives of this study were to assess navoximod's absolute bioavailability (aBA), determine the mass balance and routes of elimination of [14 C]-navoximod, and characterize navoximod's metabolite profile. METHODS: A phase 1, open-label, two-part study was conducted in healthy volunteers. In Part 1 (aBA), subjects (n = 16) were randomized to receive oral (200 mg tablet) or intravenous (5 mg solution) navoximod in a crossover design with a 5-day washout. In Part 2 (mass balance), subjects (n = 8) were administered [14 C]-navoximod (200 mg/600 µCi) as an oral solution. RESULTS: The aBA of navoximod was estimated to be 55.5%, with a geometric mean (%CV) plasma clearance and volume of distribution of 62.0 L/h (21.0%) and 1120 L (28.4%), respectively. Mean recovery of total radioactivity was 87.8%, with 80.4% detected in urine and the remainder (7.4%) in faeces. Navoximod was extensively metabolized, with unchanged navoximod representing 5.45% of the dose recovered in the urine and faeces. Glucuronidation was identified as the primary route of metabolism, with the major glucuronide metabolite, M28, accounting for 57.5% of the total drug-derived exposure and 59.7% of the administered dose recovered in urine. CONCLUSIONS: Navoximod was well tolerated, quickly absorbed and showed moderate bioavailability, with minimal recovery of the dose as unchanged parent in the urine and faeces. Metabolism was identified as the primary route of clearance and navoximod glucuronide (M28) was the most abundant metabolite in circulation with all other metabolites accounting for <10% of drug-related exposure.

Discovery of 2,4-bis-arylamino-1,3-pyrimidines as insulin-like growth factor-1 receptor (IGF-1R) inhibitors.

The insulin-like growth factor-1 receptor (IGF-1R) plays an important role in the regulation of cell growth and differentiation, and in protection from apoptosis. IGF-1R has been shown to be an appealing target for the treatment of human cancer. Herein, we report the synthesis, structure-activity relationships (SAR), X-ray cocrystal structure and in vivo tumor study results for a series of 2,4-bis-arylamino-1,3-pyrimidines.

The co-crystal approach to improve the exposure of a water-insoluble compound: AMG 517 sorbic acid co-crystal characterization and pharmacokinetics.

Co-crystals are relatively novel in the pharmaceutical field and are not reported extensively. AMG 517 is an insoluble small molecule VR1 (vanilloid receptor 1) antagonist. In animal studies, good exposure of AMG 517 is seen from a 10% (w/v) Pluronic F108 in OraPlus suspension. Investigation of the suspension formulation revealed that AMG 517 forms a co-crystal with sorbic acid, a preservative in OraPlus. This co-crystal of AMG 517 was isolated by coslurrying AMG 517 and sorbic acid; studied by DSC and XRD; and identified by solution NMR, TGA, and HPLC to be a 1:1 association of AMG 517 and sorbic acid. Single crystal structure analysis revealed a 1:1 co-crystal of AMG 517 and sorbic acid, held together by two hydrogen bonds and other noncovalent, nonionic forces. The co-crystal has better aqueous solubility initially as compared to AMG 517 free base but does revert back to a form of the free base hydrate during prolonged slurry in FaSIF (fasted simulated intestinal fluid). Pharmacokinetic evaluation of the co-crystal in rats using 10% (w/v) Pluronic F108 in OraPlus suspensions revealed that a 30 mg/kg dose in suspension had comparable exposure to a 500 mg/kg dose of the free base.