Drug migration from the adhesive matrix to the polymer film laminate facestock in a transdermal nitroglycerin system.

The apparent loss of nitroglycerin in a prototype transdermal nitroglycerin system was investigated by attenuated total reflectance infrared (ATR-IR) microspectroscopy and high performance liquid chromatography (HPLC). Several transdermal nitroglycerin lots placed under controlled storage conditions exhibited loss of drug potency (up to 10%) along with the appearance of a defect in the polymer film laminate facestock. A significant loss of nitroglycerin from the transdermal drug/adhesive matrix may reduce the bioavailabilty of nitroglycerin to the patient. ATR-IR analysis confirmed that nitroglycerin migrated from the drug/adhesive matrix to the facestock polyester layer under storage conditions and that nitroglycerin was retained in the facestock polyester layer. An alternate sample extraction solution successfully removed the nitroglycerin from both the adhesive matrix and facestock polyester layer with nearly 100% labeled strength recovered. The relationship between the migration of nitroglycerin into the facestock polyester layer and the appearance of the defect in the facestock aluminum layer is discussed and a nitroglycerin-aluminum metal reaction mechanism is proposed.

Spectroscopic identification of an amorphous-to-crystalline drug transition in a solid dispersion SCH 48461 capsule formulation.

Changes in the dissolution of a solid dispersion capsule formulation composed of amorphous SCH 48461 in a polyethylene glycol 8000 matrix were investigated. SCH 48461 [(3R,4S)-1,4-bis(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone] is a potent cholesterol absorption inhibitor with low water solubility and low melting point. Several capsule lots placed under controlled storage conditions exhibited a slowing of dissolution as a function of time with large inter-lot and intra-lot dissolution variations. Capsule contents were analyzed by attenuated total reflectance infrared (ATR-IR) microspectroscopy and solid-state cross-polarization, magic angle spinning (CPMAS) 13C-nuclear magnetic resonance (NMR) spectrometry. ATR-IR microspectroscopic analysis showed large IR spectral differences between the lots including the presence of a crystalline drug fraction in lots which exhibited incomplete dissolution. Solid-state CPMAS 13C-NMR analysis confirmed the presence of a crystalline drug fraction in the problematic capsule lots. Both ATR-IR and CPMAS 13C-NMR spectral results produced a rank ordering of the crystalline drug fraction present in the capsule lots that correspond to the dissolution results.

Antiviral phospholipids. Anti-HIV drugs conjugated to the glycerobackbone of phospholipids.

Heteroatom fatty acid analogs of myristic acid containing oxygen or sulfur substituted for the alkyl methylene groups inhibit replication of the human immunodeficiency virus (HIV) in infected cells by acting as alternative substrates during the viral protein myristoylation event. In this class of compounds, 12-methoxydodecanoic acid is the most potent compound but is approximately 10(3)-fold less active than azidothymidine. The antiviral activity of 12-methoxydodecanoic acid can be enhanced > 40-fold by preparing L-alpha-phosphatidylethanolamine containing 12-methoxydodecanoic acid in both alkyl chains. In addition, the diacylated L-alpha-phosphatidylcholine analog containing 12-methoxydodecanoic acid in both alkyl chains (i) has a 15-fold better antiviral selectivity, (ii) is 7-fold more potent, and (iii) is 10-100-fold more synergistic with azidothymidine than 12-methoxydodecanoic acid. Because of potent synergism, the antiviral selectivity of the diacylated L-alpha-phosphatidylcholine analog is > 10(4) when coadministered with azidothymidine. Phospholipid conjugates are chiral at the C-2 carbon of the glycerol backbone and most interesting is the observation that both the D- and L-isomers of phosphatidylcholine, phosphatidylglycerol, phosphatidic acid, and phosphatidylserine have approximately equal antiviral activity. Phospholipase A2 stereospecifically hydrolyzes only the L isomer of phospholipids and similar activity for both the D- and L- phospholipid isomers suggests that phospholipase A2 is not the rate-limiting enzyme for release of the drugs in vivo.

Silica subsurface amine effect on the chemical stability and chromatographic properties of end-capped immobilized artificial membrane surfaces.

The silica surface of immobilized artificial membranes containing phosphatidylcholine (IAM.PC) has approximately two aminopropyl groups per immobilized phosphatidylcholine molecule. Primary amines near the silica subsurface adsorb biomolecules and also decrease the chemical stability of IAM.PC surfaces. Consequently, subsurface amines were end-capped by several methods including silylating reagents, acetyl analogues, glycidol, methyl glycolate, short-chain anhydrides (3-6 carbons/anhydride chain), and long-chain anhydrides (10-12 carbons/anhydride chain). All end-capping reactions resulted in loss of the initially immobilized phosphatidylcholine molecule. However, the amount of PC loss during end capping was very low (for alkyl anhydride end-capping reactions) to very high (for silylation end-capping reactions). After end capping, IAM.PC showed increased chemical stability compared to non end-capped IAM.PC surfaces. The chemical stability of IAM packing material was monitored by phospholipid leaching from IAM surfaces exposed to organic and aqueous solvents using thin-layer chromatography, 1H NMR spectroscopy, infrared spectroscopy, and mass spectrometry. IAM.PC packing material end capped with long-chain anhydrides exhibited the greatest chemical stability, i.e., little or no detectable phospholipid leaching when challenged with aqueous and/or organic solvents. The chromatography of acidic and basic compounds on end-capped and non-end-capped IAM.PC surfaces was studied. Compared to non-end-capped IAM.PC HPLC columns, the chromatographic retention times of acidic compounds (deoxynucleotides) decreased after end capping. In contrast, the retention times of basic compounds (amphetamine analogues) increased on end-capped IAM.PC HPLC columns relative to non-end-capped IAM.PC HPLC columns. This indicates that these solutes have access to the silica subsurface amines during chromatography.

Introduction to Fourier transform infrared spectroscopy and applications in the pharmaceutical sciences.

The applications of infrared spectroscopy to pharmaceutical sciences is small compared to the applications of infrared spectroscopy to the fields of chemistry, biology, and biochemistry. This is unfortunate because modern routine infrared spectrometers are excellent research tools that provide very high signal-to-noise, high resolution, and extensive data-manipulation computer software packages. This review summarizes basic principles of infrared spectrometers and the use of Fourier self-deconvolution.

Formation of the antiplanar-antiplanar phosphate conformation of dilauroylphosphatidylcholine bilayers.

Infrared spectroscopy was used to investigate lipid conformational changes that occur in dilauroylphosphatidylcholine (diC12PC) bilayers with and without fatty-acid-amino-acids as guest molecules in the membrane. Incorporating 2.5 mole% N-decanoylglycine (decgly) into diC12PC liposomes caused formation of the antiplanar-antiplanar (ap-ap) phosphodiester conformation which was stable in room temperature IR spectra. Several other fatty-acid-amino-acids incorporated into diC12PC bilayers were found to also elicit the ap-ap phosphodiester conformation. Unlike these diC12PC/fatty-acid-amino-acid mixed bilayers, pure diC12PC bilayers would form the ap-ap phosphodiester conformation only under low temperature incubation conditions. Dry diC12PC films incubated at 5 degrees C for 0.5 h (brief incubation) or 16 h (prolonged incubation), and then rapidly hydrated (i.e., vortexed at 25 degrees C in D2O), caused the ap-ap phosphodiester conformation to persist in the diC12PC liposomes equilibrated to room temperature. Slow hydration for 16 h at 5 degrees C in both buffered and non-buffered D2O of diC12PC lipid films also produced the ap-ap phosphodiester conformation. In contrast, slow hydration for 16 h at 5 degrees C in PBS/D2O of diC12PC/decgly mixed films caused the greatest number of ap-ap phosphodiester conformers. Using pure diC12PC bilayers, infrared data indicate that incubation of diC12PC films causes the headgroup phosphodiester conformation to change from gauche-gauche (g-g) conformation to the ap-ap conformation. Under all liposome formation conditions examined, no changes in hydration of either the phosphate group or the carbonyl ester group were detected and in addition, no trans/gauche conformational changes in the acyl chain were observed.

Fourier transform infrared assay of membrane lipids immobilized to silica: leaching and stability of immobilized artificial membrane-bonded phases.

A nondestructive, sensitive assay to monitor the hydrocarbon content of silica-based chromatography particles has been developed. The assay requires a microscope accessory interfaced with a Fourier transform infrared (FTIR) spectrometer. For determining hydrocarbon content, undiluted alkyl-silica-bonded phases were pressed into a thin wafer. Hydrocarbon content was quantitated using the integrated hydrocarbon band intensity between 2995 and 2825 cm-1 [i.e., band area C-H] and the integrated silica oxide band intensity between 1945 and 1780 cm-1 [i.e., band area Si-O]. Plotting the [band area C-H]/[band area Si-O] ratio vs the carbon content determined by elemental analysis gave a correlation coefficient of r = 0.997. The FTIR assay was validated on 5-, 7-, and 12-microns silica particles using three different immobilized artificial membrane (IAM) silica-bonded phases. The utility of the FTIR assay in determining hydrocarbon content was demonstrated by evaluating hydrocarbon leaching from IAM phases exposed to mobile-phase solvents. The ability of organic solvents to leach hydrocarbon from IAM phases containing phosphatidylcholine (PC) as the immobilized ligand was chloroform greater than ethanol approximately methanol greater than ethyl acetate greater than methylene chloride greater than acetonitrile greater than acetone. Acetone and acetonitrile cause very little hydrocarbon leaching from HPLC-IAM.PC columns. When challenged with different mobile phases, IAM.PC columns perfused with mobile phase are more stable than IAM.PC-bonded phases stirred in mobile phases. IAM.PC contains lecithin linked to silica by amide bonds.(ABSTRACT TRUNCATED AT 250 WORDS)