Katherine Lynn Ulman

Effects of polymer structure on the gas permeability of silicone membranes

Abstract The effect of organic substituents and polymer backbone structure on the oxygen and nitrogen permeability of the following silicone polymers was investigated: Series A, (MeRSiO)x, where R is alkyl, aryl, or CH2CH2CF3; Series B, (Me2SiCnH2nSiMe2O)x, where n=2, 6 and 8; Series C, (Me2SiC6H4SiMe2O)x. It was found that as the size of the alkyl group in Series A was increased, the permeability decreased markedly, whereas the O2-N2 selectively remained more or less constant. Aryl substituents in Series A and p-silarylene linkages in Series C caused a significant decrease in permeability but an increase in the selectivity. Incorporation of organosilyl pendant groups onto organic polymers causes pronounced increases in permeability but decreases in selectivity. The cost for the oxygen enrichment of air using these silicone membranes was analyzed using computer modelling. A quantitative permeability-selectivity-cost relationship has been established.

Passive Transdermal Systems Whitepaper Incorporating Current Chemistry, Manufacturing and Controls (CMC) Development Principles

In this whitepaper, the Manufacturing Technical Committee (MTC) of the Product Quality Research Institute has updated the 1997 Transdermal Drug Delivery Systems Scale-Up and Post Approval Change workshop report findings to add important new product development and control principles. Important topics reviewed include ICH harmonization, quality by design, process analytical technologies, product and process validation, improvements to control of critical excipients, and discussion of Food and Drug Administration’s Guidance on Residual Drug in Transdermal and Related Drug Delivery Systems as well as current thinking and trends on in vitro–in vivo correlation considerations for transdermal systems.

Elemental Impurities in Pharmaceutical Excipients

Control of elemental impurities in pharmaceutical materials is currently undergoing a transition from control based on concentrations in components of drug products to control based on permitted daily exposures in drug products. Within the pharmaceutical community, there is uncertainty regarding the impact of these changes on manufactures of drug products. This uncertainty is fueled in part by a lack of publically available information on elemental impurity levels in common pharmaceutical excipients. This paper summarizes a recent survey of elemental impurity levels in common pharmaceutical excipients as well as some drug substances. A widely applicable analytical procedure was developed and was shown to be suitable for analysis of elements that are subject to United States Pharmacopoeia Chapter <232> and International Conference on Harmonizations Q3D Guideline on Elemental Impurities. The procedure utilizes microwave-assisted digestion of pharmaceutical materials and inductively coupled plasma mass spectrometry for quantitative analysis of these elements. The procedure was applied to 190 samples from 31 different excipients and 15 samples from eight drug substances provided through the International Pharmaceutical Excipient Council of the Americas. The results of the survey indicate that, for the materials included in the study, relatively low levels of elemental impurities are present.

Effect of polymer composition on steroid permeation: Membrane permeation kinetics of androgens and progestins

Abstract The permeation rates of 10 androgenic and 7 progestagenic steroids through synthetic membranes fabricated from poly(trifluoropropylmethylsiloxane) (PFMS), poly (dimethylsiloxane) (PDMS) and the copolymer of PDMS with poly(ethylene oxide) (PEO) and poly (methyl methacrylate) (PMMA) were investigated and found to be profoundly affected by the chemical structure of penetrants and/or the copolymer composition. The permeation rate for both groups of steroids was observed to decrease in the order of PDMS > PFMS > PDMS/PEO/PMMA copolymer. This can be attributed to the increase in membrane polarity, which causes a decrease in the polymer solubility of steroids, and the incorporation of the high-Tg glassy polymer segments, which leads to a reduction in the diffusivity in the polymer. The increase in the PDMS block size tends to promote the permeation of steroids, which can be explained in light of the increase in the size of more permeable PDMS domain. Incorporation of PMMA blocks into PDMS drastically decreases the rate of steroid permeation due to the presence of less permeable “hard” PMMA domains, while addition of PEO produces an enhancing effect on the permeation of less lipophilic steroids such as testosterone.

Kinetics and Thermodynamics of Drug Permeation Through Silicone Elastomers iv. Effect of Polymer Backbone Structure

AbstractThe effect of silicone polymer backbone structure on the permeability of progesterone and testosterone through silicone membranes was investigated in the capsule-type drug delivery system at 25, 37 and 50°C, respectively. Three types of polymer were studied: (I) (Me2SiCH2)x, (II) (Me2Sl-CH4-SiMe2O)x, and (III) [Me2Si(CH2)n SiMe2O] x, where n=2, 6 and 8.Permeabilities of progesterone in these polymers were found to decrease in the following order: Polymer (III) < Polymer (I) < Polymer (II). The same order was also observed for the permeabilities of testosterone, but their values were one order of magnitude lower than those of progesterone. Incorporation of the phenylene group in the polymer backbone in Polymer (II) caused a significant decrease in the diffusion coefficient but an increase in the solubility coefficient. The net effect is a 50% decrease in the permeability with respect to (Me2 SiO)x. This effect was found to be less pronounced with alkylene group in Polymer (III).The activation energ...

Drug permeability of modified silicone polymers. III. Hydrophilic pressure-sensitive adhesives for transdermal controlled drug release applications

Abstract A new class of hydrophilic silicone/organic pressure-sensitive adhesives (PSAs) was formulated from polydimethylsiloxane-poly(ethylene oxide) graft copolymers and silicone resins. The following effects of the structure of the graft copolymers and silicone resins on the adhesion and the drug permeability were investigated: (a) the size and the degree of the grafting, (b) the degree of polymerization of the polysiloxane and (c) the loading level and molecular weight of the silicone resin. It was demonstrated that a number of therapeutic agents could be incorporated into the PSAs without compromising their functional adhesive tape properties. The PSAs not only had excellent drug permeabilities but also retained their adhesion upon aging, thus permitting their use in transdermal controlled drug release applications. This family of PSAs has a distinct advantage over other PSAs because it also enhanced the release rates of hydrophilic drugs.

Kinetics and Thermodynamics of Drug Permeation Through Silicone Elastomers III. Effect of Alkyl Substituent (R) in (MeRSiO) Polymer

AbstractThe effect of silicone polymer structure on the permeability of drug through silicone membranes was investigated in the capsule-type drug delivery system. The permeability, diffusivity and solubility of progesterone and testosterone through polymethylalkylsiloxane membranes, (MeCn H2n+1 SiO)x, where n = 1, 2, 3, 6 and 8, were determined at 25, 37 and 50°C respectively.As the size of the alkyl substituent was increased from methyl to octyl, the diffusivity decreased, whereas the solubility increased. As a result, the permeability of progesterone decreased initially but increased gradually thereafter, going from (Me2SiO)x to (MeOctSiO)x, in this series of polymer. The same results were obtained with testosterone; however, permeabilities of testosterone were found to be one order of magnitude lower than those of progesterone. This was attributed to the lower solubilities of testosterone in (MeRSiO)x polymers when compared to those for progesterone. The activation energies of permeation for progestero...