Frederick G. Vogt

Analysis of Amorphous Solid Dispersions Using 2D Solid-State NMR and 1H T1 Relaxation Measurements

Solid-state NMR (SSNMR) can provide detailed structural information about amorphous solid dispersions of pharmaceutical small molecules. In this study, the ability of SSNMR experiments based on dipolar correlation, spin diffusion, and relaxation measurements to characterize the structure of solid dispersions is explored. Observation of spin diffusion effects using the 2D (1)H-(13)C cross-polarization heteronuclear correlation (CP-HETCOR) experiment is shown to be a useful probe of association between the amorphous drug and polymer that is capable of directly proving glass solution formation. Dispersions of acetaminophen and indomethacin in different polymers are examined using this approach, as well as (1)H double-quantum correlation experiments to probe additional structural features. (1)H-(19)F CP-HETCOR serves a similar role for fluorinated drug molecules such as diflunisal in dispersions, providing a rapid means to prove the formation of a glass solution. Phase separation is detected using (13)C, (19)F, and (23)Na-detected (1)H T(1) experiments in crystalline and amorphous solid dispersions that contain small domains. (1)H T(1) measurements of amorphous nanosuspensions of trehalose and dextran illustrate the ability of SSNMR to detect domain size effects in dispersions that are not glass solutions via spin diffusion effects. Two previously unreported amorphous solid dispersions involving up to three components and containing voriconazole and telithromycin are analyzed using these experiments to demonstrate the general applicability of the approach.

Development of Quality-By-Design Analytical Methods

Quality-by-design (QbD) is a systematic approach to drug development, which begins with predefined objectives, and uses science and risk management approaches to gain product and process understanding and ultimately process control. The concept of QbD can be extended to analytical methods. QbD mandates the definition of a goal for the method, and emphasizes thorough evaluation and scouting of alternative methods in a systematic way to obtain optimal method performance. Candidate methods are then carefully assessed in a structured manner for risks, and are challenged to determine if robustness and ruggedness criteria are satisfied. As a result of these studies, the method performance can be understood and improved if necessary, and a control strategy can be defined to manage risk and ensure the method performs as desired when validated and deployed. In this review, the current state of analytical QbD in the industry is detailed with examples of the application of analytical QbD principles to a range of analytical methods, including high-performance liquid chromatography, Karl Fischer titration for moisture content, vibrational spectroscopy for chemical identification, quantitative color measurement, and trace analysis for genotoxic impurities.

Probing Hydrogen Bonding in Cocrystals and Amorphous Dispersions Using 14N–1H HMQC Solid-State NMR

Cocrystals and amorphous solid dispersions have generated interest in the pharmaceutical industry as an alternative to more established solid delivery forms. The identification of intermolecular hydrogen bonding interactions in a nicotinamide palmitic acid cocrystal and a 50% w/w acetaminophen-polyvinylpyrrolidone solid dispersion are reported using advanced solid-state magic-angle spinning (MAS) NMR methods. The application of a novel (14)N-(1)H HMQC experiment, where coherence transfer is achieved via through-space couplings, is shown to identify specific hydrogen bonding motifs. Additionally, (1)H isotropic chemical shifts and (14)N electric field gradient (EFG) parameters, both accessible from (14)N-(1)H HMQC experiments, are shown to be sensitive to changes in hydrogen bonding geometry. Numerous indicators of molecular association are accessible from this experiment, including NH cross-peaks occurring from intermolecular hydrogen bonds and changes in proton chemical shifts or electric field gradient parameters. First-principles calculations using the GIPAW approach that yield accurate estimates of isotropic chemical shifts, and EFG parameters were used to assist in assignment. It is envisaged that (14)N-(1)H HMQC solid state NMR experiments could become a valuable screening technique of solid delivery forms in the pharmaceutical industry.

Design, Physicochemical Characterization, and Optimization of Organic Solution Advanced Spray-Dried Inhalable Dipalmitoylphosphatidylcholine (DPPC) and Dipalmitoylphosphatidylethanolamine Poly(Ethylene Glycol) (DPPE-PEG) Microparticles and Nanoparticles for Targeted Respiratory Nanomedicine Delivery as Dry Powder Inhalation Aerosols

Novel advanced spray-dried and co-spray-dried inhalable lung surfactant-mimic phospholipid and poly(ethylene glycol) (PEG)ylated lipopolymers as microparticulate/nanoparticulate dry powders of biodegradable biocompatible lipopolymers were rationally formulated via an organic solution advanced spray-drying process in closed mode using various phospholipid formulations and rationally chosen spray-drying pump rates. Ratios of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylethanolamine PEG (DPPE-PEG) with varying PEG lengths were mixed in a dilute methanol solution. Scanning electron microscopy images showed the smooth, spherical particle morphology of the inhalable particles. The size of the particles was statistically analyzed using the scanning electron micrographs and SigmaScan® software and were determined to be 600 nm to 1.2 μm in diameter, which is optimal for deep-lung alveolar penetration. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were performed to analyze solid-state transitions and long-range molecular order, respectively, and allowed for the confirmation of the presence of phospholipid bilayers in the solid state of the particles. The residual water content of the particles was very low, as quantified analytically via Karl Fischer titration. The composition of the particles was confirmed using attenuated total-reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy and confocal Raman microscopy (CRM), and chemical imaging confirmed the chemical homogeneity of the particles. The dry powder aerosol dispersion properties were evaluated using the Next Generation Impactor™ (NGI™) coupled with the HandiHaler® dry powder inhaler device, where the mass median aerodynamic diameter from 2.6 to 4.3 μm with excellent aerosol dispersion performance, as exemplified by high values of emitted dose, fine particle fraction, and respirable fraction. Overall, it was determined that the pump rates defined in the spray-drying process had a significant effect on the solid-state particle properties and that a higher pump rate produced the most optimal system. Advanced dry powder inhalers of inhalable lipopolymers for targeted dry powder inhalation delivery were successfully achieved.

Probing intermolecular interactions and nitrogen protonation in pharmaceuticals by novel 15N-edited and 2D 14N-1H solid-state NMR

We report the applications of two novel magic-angle spinning (MAS) solid-state NMR methods, 1J15N-1H spectral editing and 2D 14N-1H HMQC, to the characterisation of nitrogen functional groups in two pharmaceutical compounds, cimetidine and tenoxicam. The 1J15N-1H spectral editing method can readily differentiate the number of protons directly bonded to a nitrogen site and is not susceptible to motional effects. This enables confirmation of proton transfer, therefore proving or disproving amine salt formation, which is of high significance to the properties of a drug. The recently developed 2D 14N-1H HMQC method can demonstrate the presence of specific hydrogen bonding interactions and thus aid in identifying molecular association. First-principles calculations of NMR chemical shifts and quadrupolar parameters using the GIPAW method were combined with experimental data to assist with spectral assignment and the identification of the hydrogen bonding motifs.

Advanced spray-dried design, physicochemical characterization, and aerosol dispersion performance of vancomycin and clarithromycin multifunctional controlled release particles for targeted respiratory delivery as dry powder inhalation aerosols.

Respirable microparticles/nanoparticles of the antibiotics vancomycin (VCM) and clarithromycin (CLM) were successfully designed and developed by novel organic solution advanced spray drying from methanol solution. Formulation optimization was achieved through statistical experimental design of pump feeding rates of 25% (Low P), 50% (Medium P) and 75% (High P). Systematic and comprehensive physicochemical characterization and imaging were carried out using scanning electron microscopy (SEM), hot-stage microscopy (HSM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Karl Fischer titration (KFT), laser size diffraction (LSD), gravimetric vapor sorption (GVS), confocal Raman microscopy (CRM) and spectroscopy for chemical imaging mapping. These novel spray-dried (SD) microparticulate/nanoparticulate dry powders displayed excellent aerosol dispersion performance as dry powder inhalers (DPIs) with high values in emitted dose (ED), respirable fraction (RF), and fine particle fraction (FPF). VCM DPIs displayed better aerosol dispersion performance compared to CLM DPIs which was related to differences in the physicochemical and particle properties of VCM and CLM. In addition, organic solution advanced co-spray drying particle engineering design was employed to successfully produce co-spray-dried (co-SD) multifunctional microparticulate/nanoparticulate aerosol powder formulations of VCM and CLM with the essential lung surfactant phospholipid, dipalmitoylphosphatidylcholine (DPPC), for controlled release pulmonary nanomedicine delivery as inhalable dry powder aerosols. Formulation optimization was achieved through statistical experimental design of molar ratios of co-SD VCM:DPPC and co-SD CLM:DPPC. XRPD and DSC confirmed that the phospholipid bilayer structure in the solid-state was preserved following spray drying. Co-SD VCM:DPPC and co-SD CLM:DPPC dry powder aerosols demonstrated controlled release of antibiotic drug that was fitted to various controlled release mathematical fitting models. The Korsmeyer-Peppas model described the best data fit for all powders suggesting super case-II transport mechanism of controlled release. Excellent aerosol dispersion performance for all co-SD microparticulate/nanoparticulate DPIs was higher than the SD antibiotic drugs suggesting that DPPC acts as an aerosol performance enhancer for these antibiotic aerosol dry powders. Co-SD VCM:DPPC DPIs had higher aerosol dispersion parameters compared to co-SD CLM:DPPC which was related to differences in the physicochemical properties of VCM and CLM.

A review of recent advances in mass spectrometric methods for gas-phase chiral analysis of pharmaceutical and biological compounds

Chirality has been of great interest in pharmaceutical and biological sciences. The capabilities of mass spectrometry (MS) for rapid analysis of complex mixtures have encouraged its exploration for gas-phase chiral differentiation. Although particular instances of successful discrimination between enantiomers have been reported over the past three decades, a general method of quantitative chiral analysis by MS has only been demonstrated recently. This review describes the current state of the chiral MS methods without chiral chromatographic separation, which fall into five main categories: (1) the kinetic method, (2) host-guest (H-G) diastereomeric adduct formation, (3) ion/molecule (equilibrium) reactions, (4) collision-induced dissociation (CID) of diastereomeric adducts, and (5) the emerging technique for gas-phase separation using ion mobility spectrometry (IMS). It emphasizes tandem mass spectrometry (MS/MS), which provides several unique analytical advantages for quantitative chiral analysis. These include intrinsically high sensitivity, molecular specificity, and tolerance to impurities as well as the simplicity and speed of the mass spectrometric measurements. Practical prospects and current challenges in quantitative chiral MS techniques for QbD (quality-by-design)-based pharmaceutical applications are also discussed.

Preparation and Structural Characterization of Amorphous Spray-Dried Dispersions of Tenoxicam with Enhanced Dissolution

Tenoxicam is a poorly soluble nonsteroidal anti-inflammatory drug. In this work, the solubility of tenoxicam is enhanced using amorphous spray-dried dispersions (SDDs) prepared using two molar equivalents of l-arginine and optionally with 10%-50% (w/w) polyvinylpyrrolidone (PVP). When added to the dispersions, PVP is shown to improve physical properties and also assists in maintaining supersaturation in solution. The dispersions provide a twofold increase over equilibrium solubility at the same pH. The dispersions are characterized using electron microscopy, vibrational spectroscopy, diffuse-reflectance visible spectroscopy, and X-ray powder diffraction. The structures of the dispersions are probed using solid-state nuclear magnetic resonance (SSNMR) experiments applied to the (1) H, (13) C, and (15) N nuclei, including two-dimensional dipolar correlation experiments that detect molecular association and the formation of a glass solution between tenoxicam, l-arginine, and PVP. Other aspects of the amorphous structure, including hydrogen-bonding interactions and the ionization state of tenoxicam and l-arginine, are also explored using SSNMR methods. These methods are used to show that the SDDs contain an amorphous l-arginine salt of tenoxicam in a glass solution that also includes PVP when present. Finally, the dispersions show only a minor decrease in chemical stability during accelerated stability studies relative to a crystalline form of tenoxicam.

17O Solid-State NMR as a Sensitive Probe of Hydrogen Bonding in Crystalline and Amorphous Solid Forms of Diflunisal

(17)O solid-state NMR (SSNMR) can provide insight into hydrogen bonding interactions in pharmaceutical polymorphs, cocrystals, and amorphous dispersions. When combined with straightforward (17)O synthetic labeling, the use of (17)O SSNMR allows for direct study of key interactions such as hydrogen bonding in these systems. In this work, novel applications of (17)O SSNMR are demonstrated in the analysis of a polymorph of diflunisal, a cocrystal of diflunisal with pyrazinamide, and amorphous dispersions of diflunisal in two polymers. The observation of the (17)O nucleus is shown to be a highly specific and useful alternative to more conventional studies of the (1)H, (13)C, and (19)F nuclei in these systems and offers unique insight into hydrogen bonding interactions. Quantum chemical calculations are used to assess the (17)O SSNMR measurements for the polymorph of diflunisal for which a crystal structure has been previously determined. Empirical hydrogen bonding trends are then examined in the cocrystal and amorphous solid forms using (17)O NMR parameters. A novel application of (1)H-(17)O cross-polarization heteronuclear correlation (CP-HETCOR) experiments is also demonstrated for the cocrystal and two dispersions. This experiment offers specific information about proton environments in proximity to the labeled oxygen sites. The use of (17)O SSNMR techniques extends the utility of SSNMR in applications to cocrystals and amorphous dispersions.

2D solid-state NMR analysis of inclusion in drug-cyclodextrin complexes.

The solubility of drug molecules can often be improved through preparation and delivery of cyclodextrin (CD) inclusion complexes. These drug-oligosaccharide complexes can be prepared in solution and converted to the solid state via methods such as lyophilization and spray-drying, or they can be prepared directly from solids by a variety of methods. The development of drug-CD complexes as solids allows for potential advantages in dosage form design, such as the preparation of layered formulations, and it also can yield improvements in chemical and physical stability. 2D solid-state NMR (SSNMR) methods provide a direct way to probe drug-CD interactions in solid complexes through dipolar interactions between nuclei within the drug and CD molecules. In this study, 2D heteronuclear and homonuclear correlation SSNMR experiments involving (1)H, (13)C, (19)F, and (31)P nuclei are used to demonstrate the inclusion of drug within the CD cavity in a variety of powder samples. To illustrate the general applicability of the SSNMR approach presented, examples are shown for the drugs diflunisal, adefovir dipivoxil, voriconazole, dexamethasone, and prednisolone in complexes with α-CD, β-CD, and sulfobutylether-substituted β-CD. The quantitative analysis of included and free drug fractions in a solid drug-CD complex using SSNMR is also demonstrated. On the basis of these results, general approaches to the characterization of these materials using SSNMR are proposed.