Biomedical subjects

Robert A Reed

Publications and source records attributed to Robert A Reed.

28 records · Page 2Linked to original sources

PubMed2004

Identification and quantitation of extractables from cellulose acetate butyrate (CAB) and estimation of their in vivo exposure levels.

The purpose of this study was to qualitatively and quantitatively determine potential cellulose acetate butyrate (CAB) extractables in a way to meaningfully predict the in vivo exposure resulting from clinical administration. Extractions of CAB-381-20 were performed in several solvent systems, consistently resulting in the detection of three extractables. The extractables have been identified as acetic acid, butyric acid, and E-2-ethyl-2-hexenoic acid (E-EHA) by LC/UV, LC/MS and NMR. Extraction studies of CAB powders in acetonitrile/phosphate buffer demonstrated quantitative extraction in 1 h for acetic acid (approximately 150 microg/g), butyric acid (approximately 200 microg/g), and EHA (approximately 20 microg/g). Subsequently, extraction studies for CAB powders and coated tablets in USP simulated gastric and intestinal fluids were performed to evaluate potential in vivo exposure. Similarly, acetic and butyric acids were quantitatively extracted from CAB-381-20 powder after 24 h exposure in both USP simulated fluids. The amounts of EHA extracted from CAB powder after 24 h were determined to be 2 and 16 microg/g in USP simulated gastric and intestinal fluids, respectively. After 24 h exposure in USP simulated fluids, the maximum amount of EHA extracted corresponds to < 0.3 microg of EHA per tablet. Pepsin and pancreatin in USP simulated fluids had no effect on EHA extraction and quantitation.

Cellulose↗

PubMed2003

Quantification of 5-HMF and dextrose in commercial aqueous dextrose solutions.

5-Hydroxymethylfurfural (5-HMF) is the major thermal decomposition product formed in aqueous dextrose solutions during sterilization and upon storage. Current compendial tests employ a spectrophotometric assay for 5-HMF and a separate assay based on optical rotation for dextrose. Efforts herein focused on identification of approaches to simultaneously quantify both 5-HMF and dextrose in aqueous solutions. Initial studies employed anion exchange chromatography with pulsed amperometric detection (PAD). These studies showed that the low anion exchange column loading capacity and concentration mismatch of dextrose and 5-HMF in typical commercial solutions makes simultaneous quantitation impractical at a single sample concentration. However, mixed modes of detection for each analyte using refractive index (RI) detection for dextrose and UV detection for 5-HMF proved viable for simultaneous quantitation. The performance of both approaches was evaluated and extremely high sensitivity for 5-HMF demonstrated (30-50 ppb). The formation of 5-HMF upon the forced thermal decomposition of dextrose was monitored and compared with results from the USP spectrophotometric assay.

Chromatography, High Pressure Liquid↗

PubMed2003

Spectroscopic approach for on-line monitoring of particle size during the processing of pharmaceutical nanoparticles.

A novel application of near-infrared (near-IR) spectroscopy for the on-line determination of nanoparticle size of a drug compound in a high solids dispersion is described. The on-line spectroscopic technique provides real-time data for process monitoring and control and overcomes the limitations that are encountered using laboratory-based instrumentation for nanoparticle size determination. Near-IR spectroscopy is capable of providing an accuracy of 2.4 nm near the endpoint of particle production, where the volume-weighted D90 particle size is determined to be 200-220 nm. The accuracy is adequate for endpoint control, which minimizes excess processing and provides control over the particle size throughout nanoparticle production.

Drug Compounding↗

PubMed2003

Characterization of an extemporaneous liquid formulation of lisinopril.

The stability of lisinopril in an extemporaneously prepared suspension stored at or below 25 degrees C for 28 days under ambient light exposure was studied. A formulation of 1-mg/mL oral suspension was prepared from commercially available 20-mg lisinopril tablets, using Bicitra and Ora-Sweet SF as the compounding vehicles to make a final volume of 200 mL. Individual samples, stored in 8-oz amber polyethylene terephthalate bottles, were used for each test performed. All samples were stored at 25 degrees C. Appropriateness of the extemporaneous preparation method was performed by shaking three lots of each suspension for 30, 60, and 90 seconds. To test the robustness and reproducibility of the method, two chemists prepared the suspensions from the same three lots of lisinopril tablets. Chemical and physical stability were established by analyzing duplicate samples at time zero and after one, two, four, and six weeks. The solubility of lisinopril was tested from suspensions stored for four weeks. In-use stability was also examined over four weeks. Photochemical stability was examined by exposing three batches of the suspension to maximum light stress in accordance with the International Conference on Harmonization. Antimicrobial-effectiveness testing was also conducted with freshly prepared suspensions and suspensions stored for six weeks. The preparation method used was appropriate and effective. Lisinopril is fully dissolved in the suspension matrix. Satisfactory chemical, physical, and microbiological results were obtained after the suspensions were stored for six weeks at 25 degrees C and 35% relative humidity. Lisinopril suspensions extemporaneously prepared from tablets are stable for at least four weeks when stored at or below 25 degrees C under ambient light exposure.

Adult↗

PubMed2003

Approach to the determination of hydrate form conversions of drug compounds and solid dosage forms by near-infrared spectroscopy.

Near-infrared (IR) spectroscopy is used for the rapid, nondestructive identification and quantitation of the hydrate form of drug compounds forming both single and multiple hydration states. Near-IR is shown to be useful in both bulk drug and in finished solid dosage forms. The capability of near-IR to nondestructively analyze samples allows the kinetics of hydrate form conversions to be measured directly in formulated products. In addition, the environmental conditions for stability of the individual hydration states are mapped out using near-IR spectroscopy. Detailed molecular mechanisms are given to account for the near-IR spectral changes that occur upon hydration. The technique is applied in both laboratory studies as well as in a process environment for at-line analysis of active pharmaceutical ingredient hydration state during pharmaceutical processing.

Absorption↗

PubMed2002

Development and validation of a stability-indicating HPLC method for the simultaneous determination of losartan potassium, hydrochlorothiazide, and their degradation products.

Losartan potassium was the first in a new class of potent angiotensin II receptor antagonists which are well-tolerated in the treatment of hypertension. Losartan potassium is the active ingredient in tablets COZAAR and is combined with diuretic co-active hydrochlorothiazide (HCTZ) in tablets HYZAAR for increased efficacy. Losartan potassium has one main impurity and two primary degradates. HCTZ has one major degradate as well as two common process impurities. Historically, separate methods have been used for the analysis of each active and their respective impurities and degradates. The ultimate goal of this work was to develop and validate a single high-performance liquid chromatography method selective for the eight main components of tablets HYZAAR. A single method was developed to afford simultaneous quantitation of actives and degradates for each of the two existing formulations. Each method is presented herein and demonstrated to be suitable for quantitation to 0.1% levels of all relevant degradates, as well as 100% levels of respective drug substances.

Chromatography, High Pressure Liquid↗

PubMed2002

Identification by LC/MS(n) of degradates of a novel carbapenem antibiotic in an aqueous matrix.

Increased drug resistance in Staphylcocci and Enterococci to currently available antibiotics has significantly limited therapeutic options. Recently, a novel carbapenem antibiotic (Compound A) with a releasable side chain adjacent to the carbapenem was investigated to combat methicillin- and vancomycin-resistant Staphylococci and vancomycin-resistant Enterococci. The major advantage of Compound A over existing antibiotics can be attributed to the fact that cleavage of the side chain upon beta-lactam ring opening retained anti-bacterial activity while expelling the immunodominant epitope of the presumed beta-lactam hapten. In this work, LC/MS methods were developed to identify degradates of Compound A in an aqueous matrix utilized in assessing product safety and supporting analytical method and formulation development. A total of eight significant degradates were observed in this Compound A sample by LC/MS(n) and other techniques. Detailed structural analysis of degradates based upon LC/MS(n) data and other supporting results will be described in this work. Proposed molecular structures were confirmed by synthesis and use of authentic standards for several degradates. Degradates 1 and 4 were identified as degradates formed through the reversal of Michael reaction from Degradate 3 that is apparently formed by hydrolysis. Degradates 2 and 8 were found to be Hofmann elimination degradates. Degradates 5 and 6 are believed to be formed through dimerization of two parent molecules followed by the reversal of Michael reaction. Finally, Degradate 7 is attributed to a displacement reaction. Potential degradation pathways based upon these preliminary studies will also be discussed.

Carbapenems↗

PubMed2002

Rapid at-line analysis of coating thickness and uniformity on tablets using laser induced breakdown spectroscopy.

Because of the functionality of controlled release tablet coatings, it is desirable to have a rapid means of optimizing coating conditions and predicting the performance of a batch at-line, prior to exhaustive lab analysis. In this paper, Laser Induced Breakdown Spectroscopy (LIBS) was utilized for the first time as a rapid means of simultaneously determining the thickness and uniformity of an enteric coating on compressed tablets. In these studies, the core tablets contained a high concentration of calcium, and the coating contained titanium, silicon, and magnesium, all of which are excellent analytical targets for LIBS. The emission spectra of all four elements were simultaneously monitored as a function of the number of laser pulses in the same spatial location, literally drilling through the coating and into the core tablet. The depth penetration of individual laser pulses was calibrated using profilometry, and the thickness of the coating was determined by the incidence of calcium signal and simultaneous decrease in emission from the other probe elements (titanium, silicon and magnesium) as the laser penetrated the coating. Coating thickness measurements were evaluated by sampling coatings ranging from 5 to 21% (100 mg tablet weight basis). Additionally, LIBS spatial resolution capabilities were exploited to evaluate the film coat thickness uniformity across the tablet faces and edges. Furthermore, tablet to tablet uniformity differences were readily assessable. The results indicate that a change in coating application of less than 2 wt.% on a 100 mg tablet can be easily detected. The rapid analysis times for this technique (10 tablets were analyzed in under 15 min) makes it applicable for in-process evaluation of coating thickness, as well as intra- and inter-tablet coating uniformity on compressed tablets.

Calcium↗

PubMedDate not supplied

Determination of the moisture content of bromobutyl rubber stoppers as a function of processing: implications for the stability of lyophilized products.

The purpose of the present study is to apply and contrast several analytical techniques to understand the change in moisture content of 20 mm diameter bromobutyl rubber stoppers as a function of typical stopper processing conditions. Three separate methods were examined and Karl-Fischer titration and techniques based on capacitance measurements at a thin-film sensor were found to provide comparable results. Stopper moisture levels were examined in stoppers: (i) as received from the manufacturer, (ii) following steam sterilization, (iii) as a function of various drying cycles, and (iv) during simulated hold conditions prior to use. Finally, the transfer of moisture from stopper to an actual product is examined on storage and general agreement observed between stopper drying conditions and cake moisture levels.

Elastomers↗

PubMedDate not supplied

The role of excipients and package components in the photostability of liquid formulations.

A phenyl ether-based drug substance exhibits photochemical degradation in citrate buffers with both ultraviolet (300-450 nm range) and visible light (380-700 nm range) exposure, even though the drug molecule itself is non-light absorbing at wavelengths > 300 nm. The major contributors to the observed photosensitivity are the citrate buffer, parts per billion (ppb) levels of iron, oxygen, and light exposure level. Although a primary phenol photodegradate is generated, there are at least eight other species formed as well. The molecular weights and abundance of these species suggest that the product distribution is generated by the reaction of hydroxyl radicals with the drug substance. The generation of the primary photodegradate is linearly proportional to the light exposure amount for a fixed concentration of iron present in the formulation. Conversely, the amount of photodegradation is also nearly linear with iron concentration (through 200 ppb levels) for a fixed amount of light exposure. The proposed mechanism for the photochemical generation of hydroxyl radicals has precedence in the literature for similar combinations of iron, oxygen, carboxylate buffers, and light. Since the buffer salt and oxygen molecular equivalents in the product are significantly higher than the ppb levels of iron employed and more difficult to remove, the control of the extent of photodegradation largely rests on the control of trace levels of iron in the formulated product and control of light exposure. Exposure of drug solutions to a series of transition metals clearly indicates that iron is the key transition metal involved in the observed photochemistry. At manufacture, the primary source of iron is the raw materials (water, drug or excipients) used in the formulation. The level of iron for product stored in glass increases with sample age and can be attributed to iron leaching from borosilicate glass vials. Consideration of adequate light control during the manufacturing and packaging processes will be discussed and can only be defined as a function of the amount of iron present at the time of manufacture in the formulation. The generality of this chemistry to other drug candidates and in the presence of other common buffers will also be discussed.

Drug Packaging↗