Rheological temperature sweeping in a quality by design approach for formulation development and optimization.

Many topical drug products are multi-phase systems which are prone to phase separation exhibiting a high risk for not meeting the critical quality attributes (CQAs) of a pharmaceutical product such as uniform active pharmaceutical ingredient (API) distribution and physical homogeneity. In order to investigate and control these CQAs a rheological temperature sweeping (RTS) method was implemented and refined to enable quantification of these characteristics within a quality by design (QbD) approach. For method implementation, emulsion and ointment compositions were prepared within a design of experiments (DoE) and critical responses from RTS were extracted via principal component analysis (PCA) in a multivariate data analysis (MVA) approach. The span after 3 cycles of RTS on emulsions and a combination of 5 principal components (PCs) for ointments were selected as responses from PCA. The span correlates with the droplet size of selected emulsions followed during stability whereas the combination of the PCs for ointments enables a differentiation of the compositions. Identified critical material attributes (CMAs) are the emulsifier concentration of the emulsion and the liquid paraffin (LP) content of the ointments. In conclusion, RTS enables a rapid screening of liquid and semi-solid products in a quantitative manner for pharmaceutical development and formulation optimization.

DissolvIt: An In Vitro Method for Simulating the Dissolution and Absorption of Inhaled Dry Powder Drugs in the Lungs.

The main purpose of this work was to develop an in vitro method for simulating the dissolution and absorption of inhaled dry powder drugs that also mimics systemic pharmacokinetic data. A second purpose was to evaluate this method. DissolvIt® was developed as a simulation of the air-blood barrier of the upper airways, constituting: "airborne" particles deposited on a glass cover slip, a mucus simulant, a polycarbonate (basal) membrane, and a pumped albumin buffer simulating the pulmonary blood flow. The PreciseInhale® exposure system was used to aerosolize and deposit test formulations onto cover slips. The particle dissolution was observed by optical microscopy as particle disappearance, and it was started directly when the particles came into contact with the mucus simulant. Solute from the dissolving particles diffused through the barrier and was absorbed into the perfusate. The drug concentration in the perfusate over time and the remaining drug in the barrier at the end of the experiment were quantitated by using liquid chromatography-tandem mass spectrometry. Budesonide and fluticasone propionate generated different pharmacokinetic dissolution/absorption profiles in DissolvIt. This study indicates that DissolvIt simulates dissolution and absorption of drugs in the lung, and that DissolvIt also mimics pharmacokinetic profiles and parameters.

The effects of polar excipients transcutol and dexpanthenol on molecular mobility, permeability, and electrical impedance of the skin barrier.

In the development of transdermal and topical products it is important to understand how formulation ingredients interact with the molecular components of the upper layer of the skin, the stratum corneum (SC), and thereby influence its macroscopic barrier properties. The aim here was to investigate the effect of two commonly used excipients, transcutol and dexpanthenol, on the molecular as well as the macroscopic properties of the skin membrane. Polarization transfer solid-state NMR methods were combined with steady-state flux and impedance spectroscopy measurements to investigate how these common excipients influence the molecular components of SC and its barrier function at strictly controlled hydration conditions in vitro with excised porcine skin. The NMR results provide completely new molecular insight into how transcutol and dexpanthenol affect specific molecular segments of both SC lipids and proteins. The presence of transcutol or dexpanthenol in the formulation at fixed water activity results in increased effective skin permeability of the model drug metronidazole. Finally, impedance spectroscopy data show clear changes of the effective skin capacitance after treatment with transcutol or dexpanthenol. Based on the complementary data, we are able to draw direct links between effects on the molecular properties and on the macroscopic barrier function of the skin barrier under treatment with formulations containing transcutol or dexpanthenol.

Correlation between epithelial toxicity and surfactant structure as derived from the effects of polyethyleneoxide surfactants on caco-2 cell monolayers and pig nasal mucosa.

The cell toxic effects of nonionic surfactants were investigated by means of two in vitro models, namely pig nasal mucosa mounted in horizontal Ussing chambers, and Caco-2 cell monolayers. A series of homologous polyethyleneoxide (PEO) surfactants with a wide span in hydrophilic head-group size and hydrophobic chain lengths were screened for concentration-dependent effects on the transepithelial electrical resistance (TEER) and mannitol permeability across Caco-2 cell monolayers. Trends in effects on permeability in the presence of increasing surfactant concentration coincided with the effects seen on TEER. Correlation of surfactant molecular structure with cell toxicity showed the size of the PEO group to be a more critical parameter than the size of the hydrocarbon chain. More specifically, the presence of very long PEO groups (>30 EO units) were found to lead to a decrease in cell toxicity. Similar trends were observed in the studies of the effects of PEO surfactants on pig nasal mucosa mounted in horizontal Ussing chambers. However, the nasal mucosa was somewhat more tolerant towards high surfactant concentrations than the Caco-2 cells. The relation between surfactant molecular structure and cell toxic effects is discussed in terms of micellar surface adsorption and micellar solubilization. The effect of the surfactants on the solubility of budesonide was investigated at two different surfactant concentrations (0.01 and 1 mg/mL). At the lower concentration, the solubilizing capacity of all of the surfactants was marginal, and there was no correlation between solubilizing capacity and cmc. At the higher concentration, on the other hand, all surfactants substantially increased the solubility of budesonide. The C18 PEO-ester with 40 EO units in the head group was found to be an efficient micellar solubilizer for budesonide, without causing adverse effects on the Caco-2 cell monolayers.

Atomic force microscopy analysis and confocal Raman microimaging of coated pellets.

Polymer-coated pellets with different coating thicknesses have been studied regarding coating morphology and drug release properties with atomic force microscopy (AFM) and confocal Raman microscopy. The results were compared with those from scanning electron microscopy (SEM) and drug release profiles, which have been measured previously for these systems and found to vary depending on coating thickness. Results from AFM studies indicated that these pellets differ in the amount of crystalline material on the surface of the coating. The amount was found to be highest on the pellet with the thinnest coating. Confocal Raman microscopy studies confirmed that the active component (remoxipride hydrochloride monohydrate) is present at or close to the surface and that the amount is higher for the thinnest coating. AFM studies in aqueous media showed that the crystalline material on the surface was almost instantaneously dissolved and released into the liquid. AFM has proven to be a powerful tool in the study of the surface of dry formulations and in the study of the controlled release mechanism of a pharmaceutical in a liquid cell. The method can be combined with Raman, giving the added possibility to identify the chemical composition in selected small areas of the coating surface.