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Case Summary A frail 87 year-old lady presented with rest angina associated with widespread ECG change and troponin release. She failed attempts at medical therapy and therefore was referred for coronary intervention on the basis that she was not a surgical candidate. Investigation Coronary angiography demonstrated heavily calcified coronary arteries with critical disease at the distal left main stem bifurcation extending into the proximal segments of both LAD and circumflex. Diagnosis Acute coronary syndrome with extensive calcific coronary artery disease in the left main stem bifurcation. Management Sequential rotational atherectomy of the left main stem bifurcation followed by ‘Y’-stenting using three Xience Prime drug eluting stents.

A chiral HPLC method was developed for the quantitation of R(-)- and S(+)-prilocaine in human serum. The method involves sensitive and selective detection of R(-)- and S(+)-prilocaine using normal-phase chiral HPLC on a pirkle-type naphthyl ethylamine stationary phase (Sumichiral OA-4700, 250 mm x 4 mm i.d.) at ambient temperature with a flow rate of 0.8 ml min-1. A sample clean-up procedure was used for isolation of the analytes of interest from human serum using Bond-Elut C18 columns with high recovery and selectivity. The detection limits were 4 ng ml-1 for R-prilocaine and 5 ng ml-1 for S-prilocaine. The limits of quantitation were 10 ng ml-1 for both enantiomers. Linear calibration curves in the 10-1000 ng ml-1 range showed good coefficients of determination > 0.999 (n = 3). Precision and accuracy of the method were within 4-5.8% and 1.5-4.8% respectively for R(-)-prilocaine, and 2.8-5.7% and 3.2-5.2% respectively for S(+)-prilocaine.

High performance liquid chromatography procedures have been developed for the assay of propofol-thiopental sodium and propofol-ondansetron mixtures. The separation and quantitation of propofol-thiopental sodium were performed on a stable bond phenyl column at ambient temperature using a mobile phase of 55:45 v/v aqueous 0.01 M monobasic postassium phosphate pH 4 - acetonitrile at a flow rate of 1 mL/min, with detection set at 235 nm. The separation was achieved within 20 min. Propofol and thiopental sodium were linear in the 12.7 - 38 and 31.4 - 94 μ/mL ranges, respectively. Accuracy and precision were in the range 0.2 - 2.6 and 0.2 - 3.2%, respectively, for the two analytes and the limits of detection for propofol and thiopental sodium were 1210 and 317 ng/mL, respectively, based on a signal to noise ratio of 2 and a 20 μL injection. The separation and quantitation of the propofol-ondansetron mixture was achieved on a 10 μm particle size phenyl column., using a mobile phase of 50:50 v/v aqueous ...

The stability of thiopental sodium and propofol in an admixture stored in polypropylene syringes at room temperature and under refrigeration was studied. Propofol injection 10 mg/ mL and thiopental sodium 25 mg/mL were mixed to final concentrations of 5 and 12.5 mg/mL, respectively. The admixture was put into 60-mL polypropylene syringes, and two syringes were stored at 23 degrees C and two at 4 degrees C. For solutions stored at 23 degrees C, samples were taken at 0, 4, 8, 24, 48, 72, 120, 168, 216, 240, and 264 hours, and for samples stored at 4 degrees C, samples were taken at 0, 4, 8, 24, 48, 72, 120, 168, 216, and 312 hours. Drug concentrations were determined by high-performance liquid chromatography. Thiopental sodium and propofol retained > 90% of their initial concentrations for up to 312 hours at 4 degrees C. At 23 degrees C, > 90% of the initial concentration was retained by propofol for up to 120 hours and by thiopental sodium for up to 240 hours. No visual changes or significant change in pH occurred in any sample. When mixed and stored in polypropylene syringes, propofol 5 mg/mL and thiopental sodium 12.5 mg/mL were stable for up to 312 hours at 4 degrees C and for up to 120 hours at 23 degrees C.

A high performance liquid chromatographic procedure has been developed for the assay of isradipine in bulk form and tablet and capsule pharmaceutical preparations. The separation is achieved within 20 min on an octadecylsilane column at ambient temperature with a mobile phase of 60:40 v/v methanol - water, a flow rate of 1 mL/min, and detection at 325 nm. Degradation studies showed no peak interference between isradipine and degradation products. It was also determined that the excipients in the commercial tablet and capsule preparations did not interfere with the assay. The method was linear in the range 10–60 μg/mL with accuracy and precision in the 0.40 - 1.53% range.

High performance liquid chromatography procedures have been developed for the assay of morphine-ondansetron and meperidine-ondansetron mixtures in 0.9% sodium chloride injection. The separation and quantitation of morphine-ondansetron were performed on an underviatized silica column at ambient temperature using a mobile phase of 60:40 v/v 0.01 M monobasic potassium phosphate pH 4.0 - methanol at a flow rate of 1.0 mL/min with the detection set at 233 nm. The separation was achieved within 20 min. Morphine and ondansetron were linear in the 134–536 and 68–271 μg/mL ranges, respectivly. Accuracy and precision were in the range 0.04–4 and 0.2–1%, respectively, for the two analytes and the limits of detection for morphine and ondansetron were 210 and 110 ng/mL, respectively, based on a signal to noise ratio of 3 and a 20 μL injection. The separation and quantitation of the meperidine-ondansetron mixture were also achieved on an underivatized silica column at ambient temperature using a mobile phase o...

A high performance liquid chromatography procedure has been developed for the assay of an ondansetron hydrochloride and diphenhydramine hydrochloride mixture in 0.9% sodium chloride injection. The separation and quantitation were achieved on a 5-μm Spherisorb ODS-1 column at ambient temperature using a mobile phase of 60:40 v/v 0.1 M phosphate buffer pH 4.5-acetonitrile at flow rate of 1.2 mL/min. with detection of both analytes at 210 nm. The separation was achieved within 22 min. with sensitivity in the ng/mL range for each analyte. The method showed linearity for ondansetron and diphenhydramine in the 0.40–6.40 and 5.0–80.0 μg/mL ranges, respectively. Intra- and inter-day RSD values were 1.8% and 2.8–3.8% for ondansetron, and 1.4–1.7% and 2.0–2.7% for diphenhydramine, respectively. Accuracy of intra and inter-day were in the 1.0–1.6% and 1.2% for ondansetron and 0.7–2.0% and 0.3–3.8% for diphenhydramine, respectively. The limits of detection for ondansetron and diphenhydramine were 70 and 105 ...

Commercially available C18-solid-phase extraction(SPE) materials, representing packed bed, disc and membrane-types were evaluated for their applicability as effective tools in the sample preparation step of HPLC assays of selective drugs and their metabolites from aqueous and serum samples. Chlorzoxazone (I) and its metabolite 6-hydroxychlorzoxazone (II), phenylbutazone (III) and its metabolite oxyphenylbutazone (IV), and imipramine (V) and its metabolite desipramine (VI) were extracted using each SPE device. In aqueous samples, the highest recoveries of I were achieved with packed bed or C18 disc, whereas the best recoveries of II were achieved with the packed bed-C18. The highest recoveries of III and IV were achieved with packed bed-C18, disc and membrane C18, and the best recoveries of V and VI were achieved with SPEC disc -C18. In serum samples, the highest recoveries of I and II were achieved with packed bed or Empore disc -C18, the best recoveries of III and IV were achieved with packed be...

An assay of atenolol in human serum is described using a 3 μm silica column with a 60:40 v/v 6.25 mM sodium dihydrogen phosphate pH 3.0-acetonitrile mobile phase at 1 mL/min; the ultraviolet detector was set at 254 nm. Minimum detectability of the drug was estimated to be 20 ng/mL (S/N = 2). The method is linear in the 100–1000 ng/mL range (r = 0.9992, n = 9). An ethylsilane solid phase extraction column was used for sample cleanup and recovery of atenolol from serum was 103 ± 4% (n = 3). Retention times for atenolol and metoprolol (internal standard) were 6.6 and 7.5 min, respectively, and typical theoretical plates were 17,583 and 22,680, respectively. Resolution between internal standard and atenolol peaks was calculated to be 4.5. A typical analysis was completed in less than 45 min. The good sensitivity and reproducibility of the method should render it useful for the assay of atenolol levels in serum.

High Performance Liquid Chromatography procedures have been developed for the assay of ondansetron-atropine and ondansetron-glycopyrrolate mixtures in 0.9% sodium chloride injection. The separation and quantitation of the ondansetron-atropine mix was achieved on an octylsilane column at ambient temperature using a mobile phase of 60:40 v/v 0.01 M phosphate buffer, pH 4-acetonitrile at a flow rate of 1.0 mL/min with detection of the analytes at 254 nm. The separation is achieved within 15 min. The method showed linearity for ondansetron and atropine in the 266–1332 and 28–138 μg/mL ranges, respectively. Accuracy and precision were in the 0.2–5.6% and 0.4–1.8% ranges, respectively, for both drugs. The limits of detection for ondansetron and atropine were 2.1 ng/mL and 8.6 μg/mL, respectively, based on a signal to noise ratio of 3 and a 20 μL injection. The separation and quantitation of the ondansetron-glycopyrrolate mix was achieved on an octylsilane column at ambient temperature using a mobile ph...

High performance liquid chromatography procedures have been developed for the assay of morphine-hydromorphone-bupivacaine and morphine-hydromorphone-tetracaine mixtures in 0.9% sodium chloride injection. The separation and quantitation of morphine-hydromorphone-bupivacaine was performed on a phenyl column at ambient temperature using a mobile phase of 50:50 v/v 0.02M phosphate buffer pH 6.0-acetonitrile at a flow rate of 1.0 mL/min with the detection of all three analytes at 235 nm. The separation was achieved within 20 min with sensitivity in ng/mL range for each analyte. Morphine, hydromorphone and bupivacaine were linear in 5.0–51, 5.1–51.7 and 5.0–50 μg/mL ranges, respectively. Accuracy and precision were in the range 0.51–1.89 and 0.02–0.50%, respectively, for all three analytes and the limit of detection was close to 250 ng/mL for each component based on a signal to noise ratio of 3 and 20 μL injection. The separation and quantitation of morphine-hydromorphone-tetracaine was achieved on a s...

The separation of the enantiomers of three phenothiazines and a dibenzazepine were investigated on several different chiral stationary phases without the use of derivatization or column switching. The phenothiazines selected were promethazine, ethopropazine and trimeprazine and the dibenzazepine was trimipramine. Three classes of columns were studied for their ability to separate the enantiomers of these compounds: brush or Pirkle, inclusionary, and affinity types. The columns stuudied were ( α - R -naphthyl)ethylurea, ( S )- tert .-leucine-( R )-1-( α -naphthyl) ethylamine, dinitrobenzoylphenylglycine; β-cyclodextrin, β-acetylated cyclodextrin; γ-cyclodextrin; Chiralcel-OD; Chiralcel-OJ and Ovomucoid. Changes in mobile phase composition were studied on each column to determine the effects of solvents on the separation of the various enantiomers. Simplex calculations for mobile phase variations were not performed because they do not predict elution order reversals.

A high performance liquid chromatography procedure has been developed for the assay of a metoclopramide and ondansetron mixture in 0.9% sodium chloride injection. The separation and quantitation are achieved on a base deactivated octylsilane column at ambient temperature using a mobile phase of 77:23 v/v 0.01 M phosphate buffer, pH 4-acetonitrile at a flow rate of 1.0 mL/min with detection of analytes at 273 nm. The separation is achieved within 15–20 min with sensitivity in the ng/mL range for each analyte. The method showed linearity for metoclopramide and ondansetron in the 12.5–50 and 5–20 μ/mL ranges, respectively. Accuracy and precision were in the 1–2% and 0.3–1.3% ranges, respectively, for both drugs. The limits of detection for metoclopramide and ondansetron were 49 and 20 ng/mL, respectively, based on a signal to noise ratio of 3 and a 20 μL injection.

Jose Costa Jr, John Ormiston, Alexandre Abizaid, James Stewart, Daniel Chamie, Mark Webster, John Yan, Vinayak Baht, Lynn Morrison, Sara Toyloy, Stefan Verheye Instituto Dante Pazzanese de Cardiologia, Sao Paulo, Brazil, Associate Professor, University of Auckland Medical School, Auckland, New Zealand, Visiting Professor Columbia University, Sao Paulo, Brazil, Auckland City Hospital, Auckland, New Zealand, Dante Pazzanese, Sao Paulo, Brazil, Elixir Medic Corp, Sunnyvale, CA, Antwerp Cardiovascular Center, ZNA Middelheim, Antwerp, Belgium, Antwerp, Belgium

To evaluate the clinical safety and effectiveness of the DESolve™ Myolimus-Eluting Bioresorbable Coronary Scaffold (BCSS)in patients with single de novo native coronary artery lesions through clinical endpoints and multiple imaging modalities. The DESolve BCSS is a novel drug eluting device that

High performance chromatographic separations of selected cardiovascular agents (propranolol, atenolol, metoprolol, verapamil, diltiazem, nifedipine, clonidine and prazosin) on underivatized silica using aqueous phosphate buffer—acetonitrile mobile phases were studied. Mobile phases differing in organic modifier concentration, ionic strength and buffer pH were prepared and tested for chromatographic separation of selected mixtures of the analytes grouped according to pharmacological activity. The best separations of all analytes were obtained using a mobile phase of 60:40 v/v aqueous pH 3 phosphate buffer—acetonitrile at a 1.0 mL/min flow rate. Substitution of methanol for acetonitrile gave increased retention of the analytes with some reduction in column efficiency measured as plate counts. Although ion-pairing appears to be the primary interactive force between the silica column and the analytes, other forces such as hydrogen bonding and hydrophobic interactions are also involved in the separation.

The four geometric isomers of a substituted pentadienyl carboxamide were separated on an achiral aminopropyl column coupled with a silica precolumn. The R and S enantiomers of the biologically active EE isomer (RO 24–0238 and RO 24–2099) were resolved (Rs 1.65) on a cellulose-based chiral stationary phase (Chiracel OF). The coupled silica and aminopropyl columns were connected to the Chiralcel OF column through a six port switching valve that enabled transfer to the EE isomer to the chiral phase for enantiomer resolution. By examining the selectivity for separation of the geometric isomers of various achiral stationary phases using hexane-isopropanol mobile phases, a method was developed which linked the achiral separation of the geometric isomers with the chiral separation of the EE enantiomers.

A high performance liquid chromatography procedure has been developed for the assay of a vincristine, doxorubicin, and ondansetron mixture in 0.9% sodium chloride injection. The separation and quantitation are achieved on a phenyl column at ambient temperature using a mobile phase of 50:50 v/v 0.02 M phosphate buffer, pH 5.4-acetonitrile at a flow rate of 1.0 mL/min with detection of all three analytes at 233 nm. The separation is achieved within 15 min with sensitivity in the ng/mL range for each analyte. The method showed linearity for vincristine, doxorubicin, and ondansetron in the 0.36–3.6, 10.0–100, and 11.95–119.7μg/mL ranges, respectively. Accuracy and precision were in the 1–3% and 0.2–3.3% ranges, respectively, for all three compounds. The limits of detection for vincristine, doxorubicin, and ondansetron were 90, 200 and 200 ng/mL, respectively, based on a signal to noise ratio of 3 and a 20/L injection.

A high-performance liquid chromatographic method for the simultaneous determination of cefuroxime and aminophylline/theophyIline has been developed. Cefuroxime was separated from aminophylline/theophylline within 8 min using a octadecylsilane column and a mobile phase consisting of a 10:1 mixture of 0.1 M acetate buffer pH 3.4—acetonitrile at ambient temperature. Orcinol was used as internal standard and the analytes were monitored at 254 nm. The method was free of interference from degradation products related to any of the analytes. Drug to internal standard peak area ratios were linear (r2 ≥ 0.9998) for each analyte with good precision (RSD ≤ 2.1%) and accuracy (≤ 2.3%).

A high-performance thin-layer chromatographic (HPTLC) method for the determination of digoxin and its related compounds digoxigenin bisdigitoxoside (DBD) and gitoxin in digoxin drug substance and tablets was developed. Separation of the three compounds was accomplished on a C 18 wettable reversed-phase plate using water-methanol-ethyl acetate (50:48:2 v/v/v) as the mobile phase. The analytes were determined by densitometry using absorbance for digoxin and fluorescence for the two related compounds. All peaks were quantified by peak-height analysis. Linear regression analysis of the data was performed for all three compounds. The calibration range for digoxin was set at 320–480 ng per 5-mm band, equivalent to 80–120% (w/w) of a 400-ng band load, that for DBD was set at 4–12 ng per 5-mm band, equivalent to 1–3% (w/w) of the digoxin load, and that for gitoxin was set at 0.4–1.6 ng per 5-mm band, equivalent to 0.1–0.4% (w/w) of the digoxin load. The limit of quantification (LOQ) for digoxin was 64 ng per 5-mm band with a limit of detection (LOD) of 8 ng per 5-mm band. The LOQs for both DBD and gitoxin were 0.12 ng per 5-mm band with LODs of 0.4 ng per 5-mm band. The linearity range for the digoxin peak height in the absorbance mode was 0–5000 ng per 5-mm band. The linearity range for DBD and gitoxin peak heights in the fluorescence mode was 0–2000 ng per 5-mm band.

R(−)-Ondansetron and S(+)-ondansetron in human serum were resolved and quantified using a stereospecific HPLC method. Each enantiomer and the internal standard prazosin were isolated from serum using a solid-phase extraction procedure on a cyanopropyl column. Recoveries of 97, 96 and 88% were obtained for the R(−)-enantiomer, the S(+)-enantiomer, and the internal standard, respectively. A cellulose-based chiral analytical column (Chiralcel OD) was used with a mobile phase consisting of hexane—95% ethanol—2-propanol—acetonitrile (65:25:10:1, v/v). Linear calibration curves were obtained for each enantiomer in serum in the concentration range 10–200 ng/ml. The limit of quantitation of each enantiomer was 10 ng/ml. The detection limit for each enantiomer in serum using UV detection at 216 nm was 2.5 ng/ml (signal-to-noise ratio of 3).

A chiral high performance liquid chromatographic method was developed for the simultaneous assay of S(+) and R(−) albuterol in human serum. The assay utilizes solid-phase extraction on a silica column as a sample clean-up step. The chiral separation was accomplished under isocratic conditions using a Sumichiral OA 4700 column and a mobile phase consisting of 350:410:40:2 v/v/v/v hexane/methylene chloride/absolute methanol/trifluoroacetic acid at a flow rate of 1.0 mL/min. The enantiomers were measured using fluorescence detection set at 228 nm excitation and an emission filter of >280nm. Racemic atenolol was used as internal standard. Drug to internal standard peak height ratios were linear over a 2–20 ng/mL range for each enantiomer. The limit of detection of each analyte was 2.0 ng/mL (S/N = 3). The lowest quantifiable level of each enantiomer was 3 ng/mL.

A high performance liquid chromatographic procedure has been developed for the assay of norepinephrine bitartrate in 5% dextrose injection containing up to a 500 fold excess of ranitidine. The separation and quantitation are achieved on a 22-cm underivatized silica column at ambient temperature (22 ± 1°C) using a mobile phase of 50:50 v/v 5 mM phosphate buffer, pH 3.0 - acetonitrile at a flow rate of 1.0 mL/min with detection at 280nm. It was shown that the predominant mechanism of retention for the drug on silica was cation exchange. The method showed linearity for norepinephrine over the 1–128 μg/mL range (r2 = 0.9999, n = 8). Accuracy and precision were in the 0.9 – 2.3 % and 0.63 – 3.3% ranges, respectively. The limit of detection was 26 ng/mL based on a signal-to-noise ratio of 3.

A high performance liquid chromatography procedure has been developed for the assay of a dacarbazine, doxorubicin, and ondansetron mixture in 5% dextrose injection. The separation and quantitation are achieved on an 22-cm underivatized silica coiumn at ambient temperature using a mobile phase of 60:40 v/v 6.25 mM phosphate buffer, pH 3.0 -acetonitrile at a flow rate of 1.0 ml min with detection of all three analytes at 216 nm. The separation is achieved within 10 min with sensitivity in the ng/ml range for each analyte. It was shown that the predominant mechanism of retention for the analytes on silica was cation exchange. The method showed linearity for dacarbazine, doxorubicin, and ondansetron in the 0.79-7.90, 0.08-1.60, and 0.06-6.00 μg/ml ranges, respectively. Accuracy and precision were in the 0-7% and 0.4-6% ranges, respectively, for all three compounds. The limits of detection for dacarbazine, doxorubicin, and ondansetron were 12.5, 10.0 and 8.0 ng/mi, respectively, based on a signal to n...

Methods for the high performance liquid chromatographic determinations of chlorzoxazone and its 6-hydroxy metabolite in human serum and urine are presented. The separation of the analytes is achieved within 15 min on an octadecylsilane column with a mobile phase of 30:70 v/v acetonitrile - aqueous 0.05 M sodium dihydrogen phosphate at a pH 4.4 flow rate of 1 mL/min. The serum procedure utilized an octadecylsilane solid-phase extraction clean-up step with injection of the eluent onto the analytical column and detection at 280nm. The urine method uses a buffer dilution of the urine sample and direct injection onto the analytical column with detection at 295nm. Recoveries of chlorzoxazone and metabolite from serum and urine samples are in the 88–103% range. Drug to internal standard peak height ratios are linear in the 0.5 – 50 μg/mL and 5–100 μg/mL ranges for both analytes in serum and urine, respectively. Limits of quantitation for chlorzoxazone are 0.12 μg/mL in serum and 0.62 μg/mL in urine. Lim...

The analysis of chlordiazepoxide and selected chlordiazepoxide mixtures using supercritical fluid chromatography (SFC) has been investigated. The separations were carried out on four different stationary phases (SB-methyl-100, SB-biphenyl-30, SB-smectic and SB-cyanopropyl-50) with carbon dioxide as the mobile phase and flame ionization detection. The relative retention data obtained using the SFC method is compared with HPLC methods.

A high performance liquid chromatographic method was developed for the simultaneous assay of R(-)- and S(+)-albuterol in human serum. The assay involves solid phase extraction as a sample clean-up step and derivatization of racemic albuterol to its diastereomeric thioureas with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl isothiocyanate. Chromatographic separation was accomplished under isocratic conditions using an octadecylsilane column and a mobile phase consisting of 29:71 acetonitrile:distilled water containing 0.1% triethylamine, pH 4.0 (adjusted with concentrated phosphoric acid) at a flow rate of 0.8 mL/min. The diastereomers were detected using a fluorescence detector set at 223 nm excitation and no emission filter. Racemic bamethane was used as internal standard. Drug to internal standard peak-height ratios were linear over a 2-20 ng/mL range for each enantiomer. The limit of detection of each analyte was 1.0 ng/mL (S/N = 3).

The stability of ceftazidime solutions (100 and 200 mg/mL) in plastic syringes and glass vials under various storage conditions was examined. Solutions of ceftazidime 100 and 200 mg/mL in sterile water were placed in polypropylene plastic syringes or glass vials and stored (1) at 21-23 degrees C for up to 8 hours, (2) at 4 degrees C for up to 96 hours, (3) at -20 degrees C for 28 days and then 21-23 degrees C for up to 8 hours, (4) at -20 degrees C for 28 days and then 4 degrees C for up to 96 hours, (5) at -20 degrees C for 91 days and then 21-23 degrees C for up to 8 hours, or (6) at-20 degrees C for 91 days and then 4 degrees C for up to 96 hours. Samples were withdrawn from each syringe and vial at designated times and assayed by high-performance liquid chromatography. Solutions were judged to be stable if drug concentrations remained above 90% of the initial values. The number of particles in each container under each storage condition was also evaluated. Ceftazidime was stable under all storage conditions. In all containers, particulate matter was within USP specifications for small-volume injections, with no change in particle count as a result of the freezing and thawing. Ceftazidime in sterile water in either glass vials or plastic syringes is stable for 8 hours at room temperature or 96 hours at 4 degrees C when such storage occurs (1) immediately after constitution, (2) after 28 days of frozen storage, or (3) after 91 days of frozen storage.

The separation of selected oestrogens (oestrone, equilin, alpha-oestradiol, beta-oestradiol and d-equilenin) using capillary supercritical fluid chromatography (SFC) was studied. Three different stationary phases (SB-methyl-100, SB-biphenyl-30 and SB-cyanopropyl-50) were studied for the separation of the compounds. A baseline separation of the oestrogens was achieved on a SB-cyanopropyl-50 column using a carbon dioxide density gradient at an oven temperature of 73 degrees C. Typical analysis time on a 7 m column was 21 min. Retention times of each oestrogen decreased with an increase in either mobile phase density or oven temperature. Accuracy and precision of the SFC method were in the 1-5.5% range. The SFC method was applied to three different dosage forms containing oestrogens.

The analysis of diazepam, chlordiazepoxide and their by- and degradation products using supercritical fluid chromatography (SFC) was investigated. The separations were carried out using a capillary SB-cyanopropyl-50 column with carbon dioxide as mobile phase and flame ionization detection. Typical analysis time was in the range of 20-23 min. Accuracy and precision of the SFC method were both in the 1–4% range. The SFC method was then applied to dosage forms containing diazepam and chlordiazepoxide. The data obtained using the SFC methods was compared with HPLC methods.

This study involved the mixing of 1:1 combinations of Bactroban (mupirocin) Ointment 2% with various cream, lotion, ointment, gel, solution and liquid soap formulations with storage at 37 degrees C for 60 days. The mixtures were assayed for mupirocin content at 0, 15, 30, 45 and 60 days using a high-pressure liquid chromatographic (HPLC) assay. At the time of preparation of these admixtures, Bactroban Ointment is chemically and physically compatible with all of the topical dermatological products studied except for Valisone lotion where a physical incompatibility is immediately observed. Admixtures of Hibiclens liquid soap or Lotrimin solution with Bactroban Ointment were stable throughout the entire 60-day study. Combinations of Lotrimin cream, Hytone cream, Valisone ointment or Vytone cream with Bactroban Ointment also retained chemical stability of mupirocin for the entire period even though two layers were observed and mixing was required to restore a physically homogenous mixture. Other Bactroban Ointment admixtures were found to be either chemically stable for mupirocin for periods less than 60 days or physically incompatible mixtures were observed upon storage. No conclusions were drawn from these studies concerning the efficacy or safety of any of these products when used in extemporaneously prepared combinations.

This is a summary report of the conference on ‘Analytical Methods Validation: Bioavailability, Bioequivalence and Pharmacokinetic Studies.’ The conference was held from December 3 to 5, 1990, in the Washington, DC area and was sponsored by the American Association of Pharmaceutical Scientists, U.S. Food and Drug Administration, Federation Internationale Pharmaceutique, Health Protection Branch (Canada) and Association of Official Analytical Chemists. The purpose of the report is to represent our assessment of the major agreements and issues discussed at the conference. This report is also intended to provide guiding principles for validation of analytical methods employed in bioavailability, bioequivalence and pharmacokinetic studies in man and animals. The objectives of the conference were: (1) to reach a consensus on what should be required in analytical methods validation and the procedures to establish validation; (2) to determine processes of application of the validation procedures in the bioavailability, bioequivalence and pharmacokinetic studies; and (3) to develop a report on analytical methods validation (which may be referred to in developing future formal guidelines). Acceptable standards for documenting and validating analytical methods with regard to processes, parameters or data treatments were discussed because of their importance in assessment of pharmacokinetic. bioavailability, and bioequivalence studies. Other topics which were considered essential in the conduct of pharmacokinetic studies or in establishing bioequivalency criteria, including measurement of drug metabolites and stereoselectivc determinations, were also deliberated.

The aim of this study was to determine the safety and efficacy of a novel pimecrolimus-eluting stent in a porcine coronary model and in a phase I clinical trial.Rapamycin- and paclitaxel-eluting stents reduce the need for repeat intervention by limiting neointimal hyperplasia but might cause delayed healing, pre-disposing patients to late stent thrombosis. Because inflammation plays a key role in restenosis, pimecrolimus, an anti-inflammatory drug, might reduce restenosis without adversely affecting re-endothelialization.We evaluated a novel polymeric pimecrolimus-eluting stent covered with a thin parylene C diffusion barrier in a porcine coronary model and in a phase I human clinical trial. The clinical study was a prospective, nonrandomized, first-in-human hypothesis-generating study that enrolled 15 patients who had a single de novo native coronary stenosis.At 28 days and 3 months in the porcine model, histopathologic indicators predicted safety and biocompatibility when stents coated with polymer only, drug only, and 2 drug-polymer formulations were compared with bare-metal stents (BMS). In the phase I clinical trial, 15 patients had successful implantation of pimecrolimus-eluting stents. By 6 months, no patient suffered death, myocardial infarction, or stent thrombosis. However, the angiographic restenosis (61%), mean late loss (1.44 mm), and repeat target lesion revascularization (53%) were significantly higher than historical BMS controls. Whereas the primary end point was percent volume obstruction, restenosis was so severe that operators performed intravascular ultrasound examination in only 6 patients.Pimecrolimus-eluting stents induced an exaggerated neointimal hyperplasia at 6 months in comparison with historical controls.

Utibapril is a novel thiadiazoline that is currently under investigation as an antihypertensive agent. The major degradation product, a diacid FPL 63674XX, is biologically active. An HPLC method has been developed to simultaneously determine both utibapril and its diacid in rodent laboratory diet used to dose animals in long term toxicology studies. The method is based on liquid-solid extraction of the compounds followed by direct injection of the extract. Gradient elution chromatography is utilized to better separate the diacid from interferences. Recovery of utibapril and the diacid from the lab diet was found to be 97.6 ± 0.44% and 99.7 ± 2.8%, respectively (n=3) at 0.43% w/w levels. The separation is achieved on a octadecylsilane column using a flow rate of 0.75 ml/min and a column temperature of 70°C. The UV detector was set at 260 nm. A linear and step gradient program was established using mobile phases consisting of 0.05 M

High performance liquid chromatography (HPLC) stationary phases of gamma cyclodextrin, ion exchange ethylvinylbenzene/divinylbenzene (EVB/DVB) copolymer and poly (Styrene-divinylbenzene) (PRP-1) copolymer were investigated for the separation of beta lactam antibiotic epimers of cephalexin, moxalactam, ticarcillin, and carbenicillin. A combination of ion pair chromatography and inclusion complex formation improved the selectivity of moxalactam epimers on gamma cyclodextrin but had no effect on cephalexin epimers. A 10% increase in resolution was obtained for the moxalactam epimers on gamma cyclodextrin when 3mM tetrapropylammonium bromide was present in the mobile phase. Ion-exchange and reverse phase properties of the ion-exchange EVB/DVB phase coupled with perchlorate or sodium pentane sulfonate ion pair chromatography were also successful in separating some of the epimers. Retention and separation behavior of the analytes could not be easily predicted using this multiphase system. The PRP-1 pha...

Some new 9-substituted 10-methylacridinium trifluoromethanesuifonate (triflate) salts have been synthesized and shown to react in methanol with the model aromatic and aliphatic amines, aniline and n-butylamine, to form derivatives which absorb strongly at 445 and 439 nm, respectively. The color development is affected by heat and heating time and by the quantity of acridinium triflate used. A 10-50-fold molar excess of the triflate should be used and the solution heated at 60 degrees for 30 min. The linearity and reproducibility of the assay are improved by the presence of pyridine (for aniline) and triethylamine (for n-butylamine) in the reaction mixture. Beer's law is obeyed over the range 0-1860 ng/ml for aniline and 0-1440 ng/ml for n-butylamine, with each of the new reagents. The relative error and the precision of determination depends on the acridinium triflate used.

A high performance liquid chromatographic post-column fluorescent ion pair extraction system was developed for the analysis of quaternary ammonium and amine drugs in serum. A new fluorescent ion pair reagent, sodium alpha-(3,4-dimethoxyphenyl) cinnamonitrile-2'-sulfonate (DPS), was synthesized and characterized. The post-column extraction system consisted of a three-dimensional knitted teflon mixing coil and a membrane phase separator which was modified from an original literature design. Physostigmine and its metabolite eseroline were used as model cations. A solid phase extraction procedure using octadecylsilane columns was developed to extract the compounds and neostigmine bromide (internal standard) from human serum. The compounds were chromatographed on a diol column using a 80:20 aqueous phosphate buffer pH 4 absolute methanol mobile phase at a flow rate of 1 mL/min. Methylene chloride was used as the on-line extraction solvent for the DPS ion pairs formed. Fluorescence of the extracted ion pairs was measured using an excitation of 243 nm and an emission cut-off filter at 418 nm. Linearity was in the 2-100 ng/mL and 5-100 ng/mL ranges for physostigmine and eseroline, respectively. Detection limits based on a signal-to-noise ratio of 2, were 2 and 5 ng/mL, respectively. Precision of the method was found to be in the 1.5-3% range and percentage error in the 1.5-7% range for both compounds.

Patients with large intracoronary thrombi represent a difficult management problem for the interventional cardiologist. We report 10 cases of challenging thrombi treated percutaneously using varying combinations of deep guide catheter engagement, guide aspiration, dedicated catheter aspiration and withdrawal of a distal filter vascular protection device. These cases demonstrate interventional options which may be considered for such patients.

The utilization of Internal Surface Reversed Phase (ISRP) packing as a solid phase extraction (SPE) matrix was investigated. Evaluation of the relative retention of nineteen medicinal agents on ISRP material was monitored using HPLC. The effects of altering pH and/or buffer concentration on retention were further studied using verapamil, phenelzine and tamoxifen as model compounds. Spiked serum samples containing the model compounds plus amitriptyline were also subjected to ISRP-SPE and HPLC. Verapamil, phenelzine, and tamoxifen were all strongly retained on ISPR as pH increased. The buffer concentration of the sample was not as critical on retention of these compounds as pH. Verapamil was quantitatively recovered from spiked serum samples (103 /pm 8.5%, n = 6), with a limit of detection of 10 ng/mL using fluorescent detection (γex = 280 nm, γem = 310 nm). Amitriptyline recovery was also quantitative (99.0/pm 5.3%, n = 6), and its limit of detection was 10 ng\mL employing short wavelength UV dete...

The stability of ranitidine in concentrations of 0.5, 1.0, and 2.0 mg/mL in admixtures with commonly used i.v. fluids was studied. The admixture vehicles were 0.9% sodium chloride, 5% dextrose, 10% dextrose, 5% dextrose and 0.45% sodium chloride, and 5% dextrose with lactated Ringer's (DLR) injections in polyvinyl chloride bags. Three bags were prepared for each test solution and stored under each of the following conditions: seven days at room temperature (23 +/- 1 degrees C) in normal laboratory lighting, 30 days at 4 degrees C, and 60 days at -20 degrees C followed by either seven days at room temperature (in light) or 14 days at 4 degrees C. Ranitidine content was determined by high-performance liquid chromatography at several intervals. Color, clarity, and pH were also examined. Ranitidine concentrations remained greater than or equal to 90% of initial concentrations under all storage conditions except in the frozen DLR admixtures. Drug loss in the DLR admixtures was greatest at the lower ranitidine concentrations. The only visual changes were yellow color in the thawed DLR admixtures and those containing ranitidine 2.0 mg/mL in 5% dextrose and 0.45% sodium chloride. Slight increases in the pH of some admixtures were noted. Ranitidine is stable for seven days at room temperature and 30 days at 4 degrees C at all concentrations and in all vehicles studied. At the studied concentrations, the drug is stable in admixtures frozen for 60 days and stored for seven days at room temperature or 14 days refrigerated, except in DLR admixtures; these admixtures should not be stored frozen.

An HPLC procedure for the estimation of trace hydrazine levels in phenelzine sulfate drug substance has been developed. The hydrazine is derivatized at ambient temperature with salicylaldehyde, and the salazine derivative is measured using short wavelength UV (209 nm). The salazine is separated from unreacted salicylaldehyde and other compounds using a mobile phase consisting of 60:40 acetonitrile-water. The mobile phase was pumped at a flow rate of 1.0 mL/min through a 150 mm × 4.6 mm i.d. reverse phase column (5 μm octadecylsilane, 30% carbon loading). The limit of detection of salazine produced when hydrazine sulfate reacts with salicylaldehyde in an analytical sample was found to be equivalent to 10 ppm of hydrazine (based upon 100 mg of phenelzine sulfate). Absorbance and hydrazine concentration are linear over the range of 10–1000 ppm of hydrazine, with an r2 of 0.9998 (n=7) based on peak height. Five samples of phenelzine sulfate analyzed for hydrazine content with salicylaldehyde gave an ...