Influence of residual solvents on the physical properties of transdermal drug delivery systems.

The purpose of this investigation was to systematically assess the effect of residual solvents on the physical properties of a silicone adhesive-based transdermal system (TDS) containing n-heptane and o-xylene as residual solvents. The processing temperature was varied in this study to obtain various contents of residual solvents in the TDS. The adhesion performance was determined by evaluating the tack, shear, and peel of these TDS at week 0 and week 2. The adhesion measurements showed significant changes in tack values with a decrease in the contents of residual solvents, but the changes in peel and shear were insignificant. The rheological characteristics such as linear viscoelastic region, loss modulus and storage modulus were also measured. The outcome of the rheological measurements was found to be more sensitive to the changes in the contents of residual solvents in comparison to adhesion measurements. These results show that the residual solvent content may affect TDS performance and should be controlled from a product quality and performance perspective.

Analytical considerations for measuring the globule size distribution of cyclosporine ophthalmic emulsions.

Measurement of particle size and size distribution of complex drug products exhibiting complex rheological behaviors can be challenging as these properties may be beyond the theoretical assumptions of the measurement technique. Herein cyclosporine (CsA) ophthalmic emulsion was selected as a model complex system, and an in-depth assessment of particle size was performed using five fundamentally different particle sizing techniques, including dynamic light scattering (DLS), laser diffraction (LD), nanoparticle tracking analysis (NTA), cryogenic transmission electron microscopy (Cryo-TEM) and 2-dimensional diffusion ordered spectroscopy nuclear magnetic resonance (2D DOSY-NMR). The effect of various viscosity modifying and stabilizing excipients in the emulsions was assessed using four types of CsA formulations, i.e., 1) no viscosity modifying excipients, 2) carbomer copolymer type A (CCA), 3) Carbopol 1342, or 4) hydroxypropyl methyl cellulose (HMPC). In general, the variability of reported particle size increased, and is not as accurate, for emulsions dispersed in a non-Newtonian fluid and at higher emulsion concentrations. This effect was reduced in part by diluting the samples to lower volume fraction and a more Newtonian regime. To address the concern that sample dilution prior to measurement may induce physical instability in the emulsions, NTA was used to monitor average size at dilutions of up to 1:50,000. The size was found to remain constant and independent of the presence or type of stabilizer used. Cryo-TEM further confirmed that dilution did not alter particle size or morphology. Of the five evaluated techniques, Cryo-TEM and 2D DOSY NMR did not require dilution for measurement. The overestimate in DLS size measurements for certain CsA formulations was attributed to complex dispersant rheological behavior, particle-particle interactions, multiple light scattering events, and/or scattering interference from the polymers, which can be overcome by either testing under dilutions or by selecting one of the techniques less impacted by the interference of polymer.

Development and validation of a UPLC-MS method for the determination of galantamine in guinea pig plasma and its application to a pre-clinical bioavailability study of novel galantamine formulations.

To evaluate the bioavailability and pharmacokinetic profiles of two novel galantamine formulations as medical countermeasure products, an ultra-performance liquid chromatography-single quadrupole mass spectrometry (UPLC-MS) method was developed and validated for quantifying galantamine in guinea pig plasma using solid-phase extraction with a mixed mode strong cation exchange reversed-phase cartridge. Chromatographic separation was achieved on a Waters Acquity UPLC BEH C18 column maintained at 40°C. The mobile phases were solution A, acetonitrile-water, 5:95 (v/v) and solution B, acetonitrile-water 90:10 (v/v), both containing 2 mM ammonium formate and 0.2% formic acid. The mobile phase was delivered utilizing a 3 min gradient program start with 95%A-5%B at a flow rate of 0.6 mL/min. The analyte and internal standard, galantamine-d3, were detected by selected ion monitoring mode on a Waters 3100 single quadrupole mass spectrometer with positive electrospray ionization. The method was validated according to the US Food and Drug Administration bioanalytical guidance. The method was selective and was linear over the analytical range of 2-2000 ng/mL. Accuracy and precision were acceptable with intra- and inter-day accuracies between 96.8 and 101% and precisions (RSD) <4.88%. The method was successfully implemented to measure galantamine plasma levels in a series of pre-clinical bioavailability studies for the evaluation of novel galantamine formulations.

Formulation characteristics and in vitro release testing of cyclosporine ophthalmic ointments.

The aim of the present study was to investigate the relationship between formulation/process variables versus the critical quality attributes (CQAs) of cyclosporine ophthalmic ointments and to explore the feasibility of using an in vitro approach to assess product sameness. A definitive screening design (DSD) was used to evaluate the impact of formulation and process variables. The formulation variables included drug percentage, percentage of corn oil and lanolin alcohol. The process variables studied were mixing temperature, mixing time and the method of mixing. The quality and performance attributes examined included drug assay, content uniformity, image analysis, rheology (storage modulus, shear viscosity) and in vitro drug release. Of the formulation variables evaluated, the percentage of the drug substance and the percentage of corn oil in the matrix were the most influential factors with respect to in vitro drug release. Conversely, the process parameters tested were observed to have minimal impact. An evaluation of the release mechanism of cyclosporine from the ointment revealed an interplay between formulation (e.g. physicochemical properties of the drug and ointment matrix type) and the release medium. These data provide a scientific basis to guide method development for in vitro drug release testing of ointment dosage forms. These results demonstrate that the in vitro methods used in this investigation were fit-for-purpose for detecting formulation and process changes and therefore amenable to assessment of product sameness.

Quality by Design approach for studying the impact of formulation and process variables on product quality of oral disintegrating films.

The present investigation was carried out to understand the impact of formulation and process variables on the quality of oral disintegrating films (ODF) using Quality by Design (QbD) approach. Lamotrigine (LMT) was used as a model drug. Formulation variable was plasticizer to film former ratio and process variables were drying temperature, air flow rate in the drying chamber, drying time and wet coat thickness of the film. A Definitive Screening Design of Experiments (DoE) was used to identify and classify the critical formulation and process variables impacting critical quality attributes (CQA). A total of 14 laboratory-scale DoE formulations were prepared and evaluated for mechanical properties (%elongation at break, yield stress, Young's modulus, folding endurance) and other CQA (dry thickness, disintegration time, dissolution rate, moisture content, moisture uptake, drug assay and drug content uniformity). The main factors affecting mechanical properties were plasticizer to film former ratio and drying temperature. Dissolution rate was found to be sensitive to air flow rate during drying and plasticizer to film former ratio. Data were analyzed for elucidating interactions between different variables, rank ordering the critical materials attributes (CMA) and critical process parameters (CPP), and for providing a predictive model for the process. Results suggested that plasticizer to film former ratio and process controls on drying are critical to manufacture LMT ODF with the desired CQA.

Hyperspectral imaging using near infrared spectroscopy to monitor coat thickness uniformity in the manufacture of a transdermal drug delivery system.

Hyperspectral imaging using near infrared spectroscopy (NIRS) integrates spectroscopy and conventional imaging to obtain both spectral and spatial information of materials. The non-invasive and rapid nature of hyperspectral imaging using NIRS makes it a valuable process analytical technology (PAT) tool for in-process monitoring and control of the manufacturing process for transdermal drug delivery systems (TDS). The focus of this investigation was to develop and validate the use of Near Infra-red (NIR) hyperspectral imaging to monitor coat thickness uniformity, a critical quality attribute (CQA) for TDS. Chemometric analysis was used to process the hyperspectral image and a partial least square (PLS) model was developed to predict the coat thickness of the TDS. The goodness of model fit and prediction were 0.9933 and 0.9933, respectively, indicating an excellent fit to the training data and also good predictability. The % Prediction Error (%PE) for internal and external validation samples was less than 5% confirming the accuracy of the PLS model developed in the present study. The feasibility of the hyperspectral imaging as a real-time process analytical tool for continuous processing was also investigated. When the PLS model was applied to detect deliberate variation in coating thickness, it was able to predict both the small and large variations as well as identify coating defects such as non-uniform regions and presence of air bubbles.

In Vitro Drug Transfer Due to Drug Retention in Human Epidermis Pretreated with Application of Marketed Estradiol Transdermal Systems.

Study objective was to assess skin-to-skin drug transfer potential that may occur due to drug retention in human epidermis (DRE) pretreated with application of estradiol transdermal drug delivery systems (TDDS) and other estradiol transdermal dosage forms (gels and sprays). TDDS (products-A, B, and C) with varying formulation design and composition, and other estradiol transdermal products (gel and spray) were applied to heat separated human epidermis (HSE) and subjected to in vitro drug permeation study. Amounts of DRE were quantified after 24 h. The DRE with product-B was significantly (P < 0.001) higher than that with product-C, product-A, gel, and spray. However, products-A and C, gel, and spray showed almost the same (P > 0.05) amounts of DRE. A separate in vitro permeation study was carried out to determine amounts of drug transferred from drug-retaining epidermis to untreated HSE. The amounts of drug transferred, due to DRE after 8 h, with product-C were significantly (P < 0.001) higher than those with products-A and B, gel, and spray. The in vitro study results indicate a high potential of skin-to-skin drug transfer due to the DRE after labeled period of using estradiol TDDS, though the clinical relevance of these findings is yet to be determined.

Enhanced dissolution of poorly soluble antiviral drugs from nanoparticles of cellulose acetate based solid dispersion matrices.

Polysaccharide-based polymers were used to produce nanoparticles of poorly soluble antiviral drugs using a rapid precipitation process. The structure-property relationships of four novel cellulose acetate-based polymers were studied for their solubility enhancement of poorly soluble drugs. Particles were purified by dialysis, and dried powders were recovered after freeze-drying. The particle diameters were 150-200 nm. The target drug loading in the particles was 25 wt%, and the drug loading efficiencies were 80-96%. The effects of the formulation process and nanoparticle properties on drug solubility were investigated. All nanoparticles afforded increased solubility and faster release compared to pure drugs. Drug release was a function of the relative hydrophobicity (or solubility parameters) of the polymers.

Development and validation of in vitro-in vivo correlation (IVIVC) for estradiol transdermal drug delivery systems.

The objective of this study was to develop a level A in vitro-in vivo correlation (IVIVC) for drug-in-adhesive (DIA) type estradiol transdermal drug delivery systems (TDDS). In vitro drug permeation studies across human skin were carried out to obtain the percent of estradiol permeation from marketed products. The in vivo time versus plasma concentration data of three estradiol TDDS at drug loadings of 2.0, 3.8 and 7.6mg (delivery rates of 25, 50 and 100µg/day, respectively) was deconvoluted using Wagner-Nelson method to obtain percent of in vivo drug absorption in postmenopausal women. The IVIVC between the in vitro percent of drug permeation (X) and in vivo percent of drug absorption (Y) for these three estradiol TDDS was constructed using GastroPlus® software. There was a high correlation (R(2)=1.0) with a polynomial regression of Y=-0.227X(2)+0.331X-0.001. These three estradiol TDDS were used for internal validation whereas another two products of the same formulation design (with delivery rates of 60 and 100µg/day) were used for external validation. The predicted estradiol serum concentrations (convoluted from in vitro skin permeation data) were compared with the observed serum concentrations for the respective products. The developed IVIVC model passed both the internal and external validations as the prediction errors (%PE) for Cmax and AUC were less than 15%. When another marketed estradiol TDDS with a delivery rate of 100µg/day but with a slight variation in formulation design was chosen, it did not pass external validation indicating the product-specific nature of IVIVC model. Results suggest that the IVIVC model developed in this study can be used to successfully predict the in vivo performance of the same estradiol TDDS with in vivo delivery rates ranging from 25 to 100µg/day.