Multi-Solvent Microdroplet Evaporation: Modeling and Measurement of Spray-Drying Kinetics with Inhalable Pharmaceutics.

PURPOSE: Evaporation and particle formation from multi-solvent microdroplets containing solid excipients pertaining to spray-drying of therapeutic agents intended for lung delivery were studied. Various water and ethanol co-solvent systems containing a variety of actives and excipients (beclomethasone, budesonide, leucine, and trehalose) were considered. METHODS: Numerical methods were used to predict the droplet evaporation rates and internal solute transfers, and their results verified and compared with results from two separate experimental setups. In particular, an electrodynamic balance was used to measure the evaporation rates of multicomponent droplets and a monodisperse droplet chain setup collected dried microparticles for further analytical investigations and ultramicroscopy. RESULTS: The numerical results are used to explain the different particle morphologies dried from solutions at different co-solvent compositions. The obtained numerical data clearly show that the two parameters controlling the general morphology of a dried particle, namely the Péclet number and the degree of saturation, can change with time in a multi-solvent droplet. This fact complicates product development for such systems. However, this additional complexity vanishes at what we define as the iso-compositional point, which occurs when the solvent ratios and other composition-dependent properties of the droplet remain constant during evaporation, similar to the azeotrope of such systems during distillation. CONCLUSIONS: Numerical and experimental analysis of multi-solvent systems indicate that spray-drying near the iso-compositional ratio simplifies the design and process development of such systems.

Correction to: Multi-Solvent Microdroplet Evaporation: Modeling and Measurement of Spray-Drying Kinetics with Inhalable Pharmaceutics.

The Publisher regrets having introduced the following errors into the article when performing proof corrections.

Isothermal microcalorimetry of pressurized systems II: effect of excipient and water ingress on formulation stability of amorphous glycopyrrolate.

PURPOSE: Use isothermal microcalorimetry to directly evaluate the effects of excipients and water content to produce a stable amorphous glycopyrrolate pressurized metered dose inhaler (pMDI) formulation. METHODS: Amorphous glycopyrrolate particles with and without excipients (Distearoyl-sn-glycero-3-phosphatidylcholine (DSPC) or ß-cyclodextrin (ßCD)) were spray dried and cold filled along with HFA 134a into customized thermal activity monitor (TAM) measurement ampoules. When applicable, a known amount of water was also pipetted into the ampoule. Sample ampoules were hermetically sealed, equilibrated to 25°C and measured isothermally for at least 24 h using the TAM III (TA Instruments, Sollentuna, Sweden). RESULTS: Amorphous glycopyrrolate particles were highly unstable and crystallized rapidly when suspended in HFA 134a. Co-spray drying the glycopyrrolate with DSPC failed to mitigate this instability, but co-spray drying with ßCD protected the amorphous glycopyrrolate from crystallization, resulting in a stable formulation at low water contents (≤ 100 ppm). CONCLUSIONS: This study shows that isothermal microcalorimetry can easily differentiate between physically stable and unstable pMDI formulations of glycopyrrolate within a few hours. Furthermore, it allows rapid screening of various formulation factors (drug form, excipients, water ingress), which can greatly reduce the time required to develop marketable products with acceptable shelf life.

Isothermal microcalorimetry of pressurized systems I: a rapid method to evaluate pressurized metered dose inhaler formulations.

PURPOSE: The techniques available to study formulation stability in pressurized metered dose inhalers (pMDIs) are limited, due to the challenging conditions of working with high pressure propellants. Isothermal microcalorimetry is a valuable tool used to screen and aid in formulation development of solid and solution drug formulations; however there are currently no available methods to evaluate pMDIs. In this paper, we have developed a method that allows measurement of such pressurized systems. METHODS: Samples were prepared by cold filling ampoules with propellant (HFA 134a) and drugs of interest. Ampoule caps were fitted with a specific O-ring, coated with paraffin and pre-conditioned prior to measurement. Samples were equilibrated at 25°C, placed in a Thermal Activity Monitor III (TAM III) system and measured isothermally at 25°C for a period of at least 24 h. RESULTS: Using well-defined procedures and ampoule preparation techniques we were able to safely contain the volatile propellant and acquire a stable measurement baseline. We were able to rapidly determine, within 6 h, the physical stability of amorphous and crystalline drug forms of beclomethasone dipropionate and formoterol fumarate dihydrate when formulated with HFA 134a. CONCLUSIONS: Isothermal microcalorimetry in pressurized HFA propellant systems was shown to be a rapid screening tool to evaluate pMDI formulation physical stability. This method can potentially be applied to study pMDI formulation factors to expedite product development.

NanoXCT: a novel technique to probe the internal architecture of pharmaceutical particles.

PURPOSE: To demonstrate the novel application of nano X-ray computed tomography (NanoXCT) for visualizing and quantifying the internal structures of pharmaceutical particles. METHODS: An Xradia NanoXCT-100, which produces ultra high-resolution and non-destructive imaging that can be reconstructed in three-dimensions (3D), was used to characterize several pharmaceutical particles. Depending on the particle size of the sample, NanoXCT was operated in Zernike Phase Contrast (ZPC) mode using either: 1) large field of view (LFOV), which has a two-dimensional (2D) spatial resolution of 172 nm; or 2) high resolution (HRES) that has a resolution of 43.7 nm. Various pharmaceutical particles with different physicochemical properties were investigated, including raw (2-hydroxypropyl)-beta-cyclodextrin (HßCD), poly (lactic-co-glycolic) acid (PLGA) microparticles, and spray-dried particles that included smooth and nanomatrix bovine serum albumin (BSA), lipid-based carriers, and mannitol. RESULTS: Both raw HßCD and PLGA microparticles had a network of voids, whereas spray-dried smooth BSA and mannitol generally had a single void. Lipid-based carriers and nanomatrix BSA particles resulted in low quality images due to high noise-to-signal ratio. The quantitative capabilities of NanoXCT were also demonstrated where spray-dried mannitol was found to have an average void volume of 0.117 ± 0.247 µm(3) and average void-to-material percentage of 3.5%. The single PLGA particle had values of 1993 µm(3) and 59.3%, respectively. CONCLUSIONS: This study reports the first series of non-destructive 3D visualizations of inhalable pharmaceutical particles. Overall, NanoXCT presents a powerful tool to dissect and observe the interior of pharmaceutical particles, including those of a respirable size.

A Review of Methods for Evaluating Particle Stability in Suspension Based Pressurized Metered Dose Inhalers.

Advances in particle engineering techniques, such as spray drying, freeze drying and supercritical fluid precipitation, have greatly enhanced the ability to control the structure, morphology, and solid state phase of inhalable sized particles (1 - 5 µm) for formulation in pressurized metered dose inhalers (pMDI). To optimize the properties of these engineered particles for formulation in hydrofluoroalkane propellants (HFA 134a / 227) it is necessary to measure both bulk and individual particle properties before, after, and during formulation. This review examines established and recently developed methods for evaluating a variety of particle properties including but not limited to size, surface and internal morphology, chemical composition, and solid state phase. Novel methods for evaluating particle physical and chemical stability directly in propellant or similar environments are also discussed.

Predicting physical stability in pressurized metered dose inhalers via dwell and instantaneous force colloidal probe microscopy.

Colloidal probe microscopy (CPM) is a quantitative predictive tool, which can offer insight into particle behavior in suspension pressurized metered dose inhalers (pMDIs). Although CPM instantaneous force measurements, which involve immediate retraction of the probe upon sample contact, can provide information on inter-particle attractive forces, they lack the ability to appropriately imitate all critical particle pMDI interactions (e.g., particle re-dispersion after prolonged pMDI storage). In this paper, two novel dwell force techniques - indentation and deflection dwell - were employed to mimic long-term particle interactions present in pMDIs, using particles of various internal structures and a model liquid propellant (2H,3H perfluoropentane) as a model system. Dwell measurements involve particle contact for an extended period of time. In deflection dwell mode the probe is held at a specific position, while in indentation dwell mode the probe is forced into the sample with a constant force for the entirety of the contact time. To evaluate the applicability of CPM to predict actual pMDI physical stability, inter-particle force measurements were compared with qualitative and quantitative bulk pMDI measurement techniques (visual quality and light scattering). Measured instantaneous attractive (snap-in) and adhesive (max-pull) forces decreased as a function of increasing surface area, while adhesive forces measured by indentation dwell decreased as a function of dwell contact time for particles containing voids. Instantaneous force measurements provided information on the likelihood of floccule formation, which was predictive of partitioning rates, while indentation dwell force measurements were predictive of formulation re-dispersibility after prolonged storage. Dwell force measurements provide additional information on particle behavior within a pMDI not obtainable via instantaneous measurements.

Quantitative and qualitative examination of particle-particle interactions using colloidal probe nanoscopy.

Colloidal Probe Nanoscopy (CPN), the study of the nano-scale interactive forces between a specifically prepared colloidal probe and any chosen substrate using the Atomic Force Microscope (AFM), can provide key insights into physical interactions present within colloidal systems. Colloidal systems are widely existent in several applications including, pharmaceuticals, foods, paints, paper, soil and minerals, detergents, printing and much more.1-3 Furthermore, colloids can exist in many states such as emulsions, foams and suspensions. Using colloidal probe nanoscopy one can obtain key information on the adhesive properties, binding energies and even gain insight into the physical stability and coagulation kinetics of the colloids present within. Additionally, colloidal probe nanoscopy can be used with biological cells to aid in drug discovery and formulation development. In this paper we describe a method for conducting colloidal probe nanoscopy, discuss key factors that are important to consider during the measurement, and show that both quantitative and qualitative data that can be obtained from such measurements.

Attachment of micro- and nano-particles on tipless cantilevers for colloidal probe microscopy.

HYPOTHESIS: Current colloidal probe preparation techniques face several challenges in the production of functional probes using particles ⩽5 µm. Challenges include: glue encapsulated particles, glue altered particle properties, improper particle or agglomerate attachment, and lengthy procedures. We present a method to rapidly and reproducibly produce functional micro and nano-colloidal probes. EXPERIMENTAL: Using a six-step procedure, cantilevers mounted on a custom designed 45° holder were used to approach and obtain a minimal amount of epoxy resin (viscosity of ∼14,000 cP) followed by a single micron/nano particle on the apex of a tipless cantilever. The epoxy and particles were prepared on individual glass slides and subsequently affixed to a 10× or 40× optical microscope lens using another custom designed holder. Scanning electron microscopy and comparative glue-colloidal probe measurements were used to confirm colloidal probe functionality. FINDINGS: The method presented allowed rapid and reproducible production of functional colloidal probes (80% success). Single nano-particles were prominently affixed to the apex of the cantilever, unaffected by the epoxy. Nano-colloidal probes were used to conduct topographical, instantaneous force, and adhesive force mapping measurements in dry and liquid media conveying their versatility and functionality in studying nano-colloidal systems.