The synthonic modeling approach provides a molecule-centered understanding of the surface properties of crystals. It has been applied extensively to understand crystallization processes. This study aimed to investigate the functional relevance of synthonic modeling to the formulation of inhalation powders by assessing cohesivity of three active pharmaceutical ingredients (APIs, fluticasone propionate (FP), budesonide (Bud), and salbutamol base (SB)) and the commonly used excipient, α-lactose monohydrate (LMH). It is found that FP (-11.5 kcal/mol) has a higher cohesive strength than Bud (-9.9 kcal/mol) or SB (-7.8 kcal/mol). The prediction correlated directly to cohesive strength measurements using laser diffraction, where the airflow pressure required for complete dispersion (CPP) was 3.5, 2.0, and 1.0 bar for FP, Bud, and SB, respectively. The highest cohesive strength was predicted for LMH (-15.9 kcal/mol), which did not correlate with the CPP value of 2.0 bar (i.e., ranking lower than FP). High FP-LMH adhesive forces (-11.7 kcal/mol) were predicted. However, aerosolization studies revealed that the FP-LMH blends consisted of agglomerated FP particles with a large median diameter (∼4-5 μm) that were not disrupted by LMH. Modeling of the crystal and surface chemistry of LMH identified high electrostatic and H-bond components of its cohesive energy due to the presence of water and hydroxyl groups in lactose, unlike the APIs. A direct comparison of the predicted and measured cohesive balance of LMH with APIs will require a more in-depth understanding of highly hydrogen-bonded systems with respect to the synthonic engineering modeling tool, as well as the influence of agglomerate structure on surface-surface contact geometry. Overall, this research has demonstrated the possible application and relevance of synthonic engineering tools for rapid pre-screening in drug formulation and design.

A novel approach is described for the quantitative bioanalysis of drugs in blood samples by ionization of the analytes collected on solid-phase microextraction (SPME) fibers by mass spectrometry (MS). The technique combines the attractive features of SPME microsampling using minimal sample volumes with the speed, selectivity, and sensitivity capabilities of MS detection. The method reported in this study involved generating gas-phase ions directly from SPME fibers without the need for any additional sample preparation or chromatographic separation; the entire process was completed within 5 min. Traditionally, analytes extracted by SPME fibers are desorbed by washing with suitable solvents followed by a transfer into a sample vial and subsequent liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to quantify the amount of analyte extracted and thereby determining the analyte concentration in the matrix. These sample preparation steps are completely eliminated by inserting the SPME fiber directly into the MS. Physiologically relevant concentrations of metoprolol and propranolol in blood samples were measured over several orders of magnitude down to concentration levels of 10 ng/mL. This preliminary assessment of direct SPME-MS showed high sensitivity (ng/mL), acceptable reproducibility (<30%), and lack of carryover. This novel approach simplifies current bioanalytical procedures providing time and cost savings. It demonstrates considerable potential for qualitative and quantitative pharmaceutical bioanalysis as well as other areas of challenging environmental and food analysis.

Graphical abstract

The size of aerosol particles prior to, and during, inhalation influences the site of deposition within the lung. As such, a detailed understanding of the hygroscopic growth of an aerosol during inhalation is necessary to accurately model the deposited dose. In the first part of this study, it is demonstrated that the aerosol produced by a nebulizer, depending on the airflows rates, may experience a (predictable) wide range of relative humidity prior to inhalation and undergo dramatic changes in both size and solute concentration. A series of sensitive single aerosol analysis techniques are then used to make measurements of the relative humidity dependent thermodynamic equilibrium properties of aerosol generated from four common nebulizer formulations. Measurements are also reported of the kinetics of mass transport during the evaporation or condensation of water from the aerosol. Combined, these measurements allow accurate prediction of the temporal response of the aerosol size prior to and during inhalation. Specifically, we compare aerosol composed of pure saline (150 mM sodium chloride solution in ultrapure water) with two commercially available nebulizer products containing relatively low compound doses: Breath®, consisting of a simple salbutamol sulfate solution (5 mg/2.5 mL; 1.7 mM) in saline, and Flixotide® Nebules, consisting of a more complex stabilized fluticasone propionate suspension (0.25 mg/mL; 0.5 mM in saline. A mimic of the commercial product Tobi© (60 mg/mL tobramycin and 2.25 mg/mL NaCl, pH 5.5-6.5) is also studied, which was prepared in house. In all cases, the presence of the pharmaceutical was shown to have a profound effect on the magnitude, and in some cases the rate, of the mass flux of water to and from the aerosol as compared to saline. These findings provide physical chemical evidence supporting observations from human inhalation studies, and suggest that using the growth dynamics of a pure saline aerosol in a lung inhalation model to represent nebulizer formulations may not be representative of the actual behavior of the aerosolized drug solutions.

We report the detection and analysis of a suspected counterfeit sample of the antimalarial medicine Metakelfin through developing nitrogen-14 nuclear quadrupole resonance ((14)N NQR) spectroscopy at a quantitative level. The sensitivity of quadrupolar parameters to the solid-state chemical environment of the molecule enables development of a technique capable of discrimination between the same pharmaceutical preparations made by different manufacturers. The (14)N NQR signal returned by a tablet (or tablets) from a Metakelfin batch suspected to be counterfeit was compared with that acquired from a tablet(s) from a known-to-be-genuine batch from the same named manufacturer. Metakelfin contains two active pharmaceutical ingredients, sulfalene and pyrimethamine, and NQR analysis revealed spectral differences for the sulfalene component indicative of differences in the processing history of the two batches. Furthermore, the NQR analysis provided quantitative information that the suspected counterfeit tablets contained only 43 ± 3%, as much sulfalene as the genuine Metakelfin tablets. Conversely, conventional nondestructive analysis by Fourier transform (FT)-Raman and FT-near infrared (NIR) spectroscopies only achieved differentiation between batches but no ascription. High performance liquid chromatography (HPLC)-UV analysis of the suspect tablets revealed a sulfalene content of 42 ± 2% of the labeled claim. The degree of agreement shows the promise of NQR as a means of the nondestructive identification and content-indicating first-stage analysis of counterfeit pharmaceuticals.