Detection and Characterization of an Unknown Impurity in Levothyroxine Oral Solution Product: Implications for Formulation Development and Storage.

An existing USP(2010) impurity method for levothyroxine drug substance was modified to expand its applicability for the analysis of levothyroxine oral solution (OS) formulation while achieving desirable resolution between the components of OS formulation. When analyzed using modified USP(2010) method, an unknown impurity was detected in one of the levothyroxine OS products. A systematic investigation of unknown impurity was carried out using a combination of chromatographic, mass spectral and physicochemical methods to understand the nature of this unknown impurity.

Nucleophilic Addition in Aqueous Apomorphine Formulation Solutions in the Presence of Sodium Metabisulfite: Implications for Formulation Development and Manufacturing.

The purpose of this study was to investigate a potential nucleophilic addition mechanism in aqueous apomorphine formulation solutions in the presence of widely used antioxidants such as sodium metabisulfite (NaSO). The findings of this investigation provide insights into how sodium metabisulfite can influence the formation of particulate under the conditions leading to the auto-oxidation of apomorphine to apomorphine orthoquinone. The addition products resulting from the reaction of bisulfite nucleophile on apomorphine orthoquinone in a Michael addition fashion were identified and characterized using ultraviolet-visible spectroscopy and mass spectrometry.

In vitro methods can forecast the effects of intragastric residence on dosage form performance.

Intragastric conditions can affect the performance of solid dosage forms. For two cases, the ability of in vitro methods to forecast these effects was investigated: first, the ability of cholestyramine to sequester bile salts in the fed small intestine and, second, disintegration times of hard gelatin capsules. After incubating cholestyramine for 90 min in milk gradually digested with pepsin, the binding of taurocholates from fed state simulating intestinal fluid onto the resin became non-specific and the affinity constant was reduced from 220 l/mole (without prior incubation) to 60 l/mole.

Gamma scintigraphy for testing bioequivalence: a case study on two cromolyn sodium nasal spray preparations.

The present work was carried out to study the deposition patterns and clearance of technetium-99m (99mTc) DTPA labeled cromolyn sodium (CS) solutions when administered from two different CS nasal products using gamma scintigraphy. Five healthy volunteers received a single dose with complete crossover design involving treatment A (test formulation) and treatment B (reference formulation). The deposition patterns as well as the changes in distribution of the radiolabeled CS solutions due to the mucociliary transport were monitored by gamma scintigraphy.

Vaginal distribution of Replens and K-Y Jelly using three imaging techniques.

Background: Determination of vaginal distribution is important to the development of potential vaginal microbicidal or spermicidal products.

Study Design: This was a descriptive study of three imaging techniques with a randomized crossover assignment of two gels and activity status within each technique.

Method: Each of three sites utilized one technique.

Investigation of human pharmacoscintigraphic behavior of two tablets and a capsule formulation of a high dose, poorly water soluble/highly permeable drug (efavirenz).

Human pharmacoscintigraphic behavior of two tablets and a capsule formulation of a high dose, poorly water soluble, highly permeable, micronized drug (efavirenz) was investigated. The tablets and capsule, prepared with samarium oxide and neutron activated to produce radioactive samarium-153, were evaluated for their in vivo disintegration and gastrointestinal (GI) transit in healthy subjects under fasted condition. Scintigraphic images were acquired to coincide with blood sampling times to assess the plasma concentration-time profile in relation to in vivo disintegration and GI transit.

Coprecipitation of nonoxynol-9 with polyvinylpyrrolidone to decrease vaginal irritation potential while maintaining spermicidal potency.

The aim of this study was to test the hypothesis that polyvinylpyrrolidone (PVP) would increase the critical micelle concentration (CMC) of nonoxynol-9 (N-9), providing a reduction in its irritation potential, while maintaining essential spermicidal activity. Solid coprecipitates of N-9 with PVP were manufactured with the use of a modified lyophilization process. The irritation potential of N-9 was estimated by an in vitro assay, monitoring the extent of hemolysis of red blood cells.

Kinetics of paclitaxel 2'-N-methylpyridinium mesylate decomposition.

This study was designed to examine the kinetics of decomposition of paclitaxel 2'-N-methylpyridinium mesylate (PNMM), a derivative of paclitaxel. Further, the potential for PNMM to act as a prodrug of paclitaxel was assessed in vitro. Stability studies of PNMM were conducted over a pH range of 4.

Evaluation of the in vivo disintegration of solid dosage forms of a bile acid sequestrant in dogs using gamma-scintigraphy and correlation to in vitro disintegration.

Purpose: [corrected] To evaluate the in vivo disintegration behavior of tablets and capsules of a bile acid sequestrant, DMP 504, in beagle dogs and to assess the significance of the in vitro disintegration of the dosage forms on subsequent in vivo behavior in order to draw possible in vitro-in vivo correlations.

Methods: Tablet and capsule formulations of a bile acid sequestrant, DMP 504, were formulated with samarium oxide and neutron activated to produce radioactive 53Sm to noninvasively evaluate their in vivo behavior in beagle dogs by gamma-scintigraphy. A four-way crossover design was completed (n = 4) in which (a) tablets from two different batches were administered under the fasted condition and manufactured using different lots of drug substance where one batch exhibited relatively faster in vitro disintegration time (30 min) than the other tablet batch, which resulted in slower disintegration (45 min), (b) a capsule formulation was administered to fasted beagles, and (c) the tablet having slower in vitro disintegration was also administered in the fed state, and its in vivo disintegration was compared to that observed in the fasted state.

Synthesis of novel iodinated derivatives of nonoxynol-9 and their bioavailability in rats.

The absorption and distribution of iodinated derivatives of nonoxynol-9, after vaginal administration in rats, were compared with results reported for [14C] nonoxynol-9. Mono-iodinated nonoxynol-9 was synthesized in addition to the radiolabeled derivative incorporating iodide-125 ([125I]). Six hours after dosing, test rats were euthanized and selected tissues were excised and assessed for radioactivity.

Synthesis and in-vitro evaluation of novel low molecular weight thiocarbamates as inhibitors of human leukocyte elastase.

A series of novel low molecular weight thiocarbamate esters (1e-6e) were synthesized and evaluated as inhibitors of human leukocyte elastase (HLE). The thiocarbamate esters studied consist of a substituted primary or secondary aliphatic or aromatic amine and a 1-phenyl-1H-tetrazole-5-thiol (Table I). The HLE catalyzed hydrolysis of N-methoxysuccinyl- L-Ala-L-Ala-L-Pro-L-Val-p-nitroanilide substrate was utilized as the measure of inhibition.

Synthesis and Mechanism of Action of Novel Thiocarbamate Inhibitors of Human Leukocyte Elastase.

Several peptidyl thiocarbamate inhibitors of human leukocyte elastase were synthesized in the molecular weight range of 700-800. Two different sequences with lysine at the P(3) and ornithine at the P(4) positions were synthesized. Most of the inhibitors with large molecular weights showed high inhibitory capacity with Ki values as low as 10(-8) M.

Bioequivalence study of stressed and nonstressed hard gelatin capsules using amoxicillin as a drug marker and gamma scintigraphy to confirm time and GI location of in vivo capsule rupture.

Purpose: Evaluate if crosslinked hard gelatin capsules (HGCs) having different in vitro dissolution profiles changed in vivo release times or altered bioavailability of a drug marker; assess if a two-tier dissolution test (with and without enzyme) predicted in vivo performance.

Methods: Two classifications of stressed HGCs were artificially produced by exposure to formaldehyde (HCHO). HGCs were categorized as, a) pass/pass (p/p) which met in vitro dissolution criterion (75% drug dissolution at 45 min), b) moderately crosslinked fail/pass (f/p) which failed dissolution criterion in the absence of enzymes and passed in the presence of enzymes, and c) severely crosslinked fail/fail (f/f) which failed in vitro standards with or without enzymes.

Synthesis and mechanism of action of novel thiocarbamate inhibitors of human leukocyte elastase.

Several peptidyl thiocarbamate inhibitors of human leukocyte elastase were synthesized in the molecular weight range of 700-800. Two different sequences with lysine at the P3 and ornithine at the P4 positions were synthesized. Most of the inhibitors with large molecular weights showed high inhibitory capacity with Ki values as low as 10(-8)M.

Novel vaginal controlled-delivery systems incorporating coprecipitates of nonoxynol-9.

The purpose of this study was to formulate Nonoxynol-9 (N-9) into a solid coprecipitate form which can be used in preparing pharmaceutically attractive and nonirritating vaginal controlled-release delivery systems (DDSs) such as gelatin capsules (HGC) and tablets. N-9 was coprecipitated with polyvinylpyrrolidone (PVP) with or without iodine to produce solid powders which were incorporated into either (a) bilayer tablet DDSs which possess a fast- (outer) and slow- (inner core) releasing compartment, and (b) HGC DDSs (named Triad HGC) composed of fast- (outer), intermediate- (granules), and slow- (pellets) releasing compartments. The rates of release of iodine and/or [14C]N-9 from the two DDSs were studied in vitro in phosphate buffer at pH 5.

Evaluation of the feasibility and use of a prototype remote drug delivery capsule (RDDC) for non-invasive regional drug absorption studies in the GI tract of man and beagle dog.

Purpose: Evaluate a prototype Remote Drug Delivery Capsule (RDDC) for use in beagle dogs and human volunteers for non-invasive drug absorption studies in different regions of the gastrointestinal tract.

Methods: The device was dual radiolabeled and GI transit of the RDDC was monitored by gamma scintigraphy. Beagles were used initially to demonstrate the functional utility of the device where a solution of ranitidine hydrochloride (150 mg) was non-invasively delivered to the stomach, proximal small intestine and distal small intestine.

In vivo evaluation of the absorption and gastrointestinal transit of avitriptan in fed and fasted subjects using gamma scintigraphy.

The study was conducted to assess the bioavailability of avitriptan after a standard high fat meal, in relation to gastrointestinal transit. Six healthy male subjects were enrolled in a four-period study with a partial replicate design where each was administered 150-mg avitriptan capsule (i) after an overnight fast, (ii) 5 min after a standard high-fat breakfast, and (iii) 4 hr after a standard high fat breakfast. The treatment administered in Period 3 was repeated in Period 4 to assess intrasubject variations in pharmacokinetics and gastrointestinal (GI) transit.

Detection of formaldehyde-induced crosslinking in soft elastic gelatin capsules using near-infrared spectrophotometry.

The purpose of this research was to monitor the migration of formaldehyde from a polyethylene glycol (PEG) fill into the gelatin shell of a soft elastic gelatin capsule (SEGC) using near-infrared (NIR) spectrophotometry. SEGCs were filled with five solutions of aqueous formaldehyde in PEG (0, 0.05, 0.

Complications of vascular access in hemodialysis (HD)--aged vs adult patients.

Reports on the success of permanent vascular access in elderly HD patients vary considerably. We reviewed the records of 149 patients [62F and 87M] aged 20-89 years old (median 59) who were on hemodialysis for 6-242 (49 median) months, and had undergone 202 vascular access procedures (177 Cimmino-Brescia fistulae and 25 PTFE grafts). Patients were divided into two groups according to the age they started HD.

Determination of extent of formaldehyde-induced crosslinking in hard gelatin capsules by near-infrared spectrophotometry.

Purpose: To predict the degree of crosslinking from formaldehyde-stressed hard gelatin capsules (HGCs) using near-infrared spectrophotometry (NIR).

Methods: HGCs were exposed to a 150 ppb atmosphere of formaldehyde for 2.25, 4.

Synthetic macromolecular inhibitors of human leukocyte elastase. 2. Effect of loading of a peptidyl carbamate inhibitor and molecular size of polymer backbone on its inhibitory capacity.

Several macromolecular inhibitors of human leukocyte elastase (HLE) were prepared by covalently bonding a low molecular weight HLE inhibitor peptidyl carbamate, p-nitrophenyl-N-[succinyl-L-alanyl-L-ananyl-L-prolylmethyl]- N-isopropyl carbamate 1, with the neutral hydrophilic polymer, poly-alpha,beta-[N-(2-hydroxyethyl)-D,L-aspartamide], PHEA 2. These novel polymeric compounds differed in the molecular size of their PHEA polymer backbone and the extent of loading of the peptidyl carbamate, (PC). They were shown to efficiently inhibit HLE (Ki = 97 to 12.

On the usefulness of glycylglycine in hemodialysis and peritoneal dialysis solutions.

This article reviews current knowledge on the usefulness of glycylglycine in preparing single stable hemodialysis (HD) and peritoneal dialysis (PD) solutions containing bicarbonate. The coexistence of bicarbonate and glycylglycine in a dialysis solution renders it a potent, stable buffer in which the well known reactions between bicarbonate and calcium and magnesium, and the subsequent formation of insoluble neutral calcium and magnesium carbonate salts, are avoided. Single stable bicarbonate-glycylglycine (BiGG) solutions for HD and PD have been successfully prepared and studied, both experimentally and clinically.

Assessment of new formulations of nonoxynol-9 coprecipitated with polyvinylpyrrolidone and iodine as possible vaginal contraceptives.

Objective: To assess the in vitro spermicidal activity of new formulations of nonoxynol-9, coprecipitated with polyvinylpyrrolidone (PVP) or iodinated PVP, against human spermatozoa via the use of the Sander-Cramer test and the cervical mucus penetration test.

Design: Solutions of PVP-nonoxynol-9 and iodinated PVP-nonoxynol-9 containing nonoxynol-9 whole molecule (oligomers 1 to 18) and its isolated fractions (oligomers 8 to 10, 4 to 6, and 1 to 3) at various concentrations (microgram/mL) were prepared via serial dilutions. Spermicidal solutions were mixed with human semen to determine the minimal lethal dose (microgram/mL).

Comparative spermicidal performance of iodinated and non-iodinated contraceptive formulations of nonoxynol-9 co-precipitated with polyvinylpyrrolidone.

The objective of this study was to evaluate the spermicidal qualities of various combinations of nonoxynol-9 (N-9; whole molecule = oligomers 1-18) and its isolated fractions (oligomers 8-10, 4-6 and 1-3), co-precipitated with non-iodinated and/or iodinated (Io) polyvinylpyrrolidone (PVP) as possible vaginal contraceptives. Spermicidal qualities of known equimolar concentrations of various combinations of PVP/N-9 and PVP-Io/N-9 were tested via a modified Sander-Cramer test (SCT) using human spermatozoa. Spermicidal agents and semen samples were mixed 1:1 (v/v) and evaluated for sperm viability.