Aspirin Products Research Articles

Synthesis of Aspirin: A General Chemistry Experiment

An experiment is described that is suitable for the early portion of the laboratory in a general chemistry course and integrates organic examples. It is the two-step synthesis of aspirin starting from oil of wintergreen. The mechanism for this synthesis provides examples of three major classes of chemical reactions: hydrolysis, condensation, and proton transfer. To understand the chemistry, the student must be able to recognize the common molecular framework shared by oil of wintergreen, salicylic acid, and aspirin and to identify the -OH and -CO2 sites where chemical changes occur. The experiment differs in three ways from traditional aspirin synthesis experiments for general chemistry. It is designed to be performed early rather than late; it starts from a naturally occurring material and requires two steps rather than one; and it utilizes FTIR spectroscopy to distinguish among oil of wintergreen starting material, salicylic acid intermediate, and aspirin product. The use of FTIR spectroscopy introduces...

A Guided Inquiry Approach to NMR Spectroscopy

We present a novel way to introduce NMR spectroscopy into the general chemistry curriculum as part of a week-long aspirin project in our one-semester introductory course. Aspirin is synthesized by reacting salicylic acid and acetic anhydride. Purity is determined by titration and IR and NMR spectroscopy. Students compare IR and NMR spectra of their aspirin product to a series of reference spectra obtained by the class. Students are able to interpret the IR spectra of their aspirin using IR data from previous experiments. NMR is introduced by having students collect 1H NMR spectra of a series of reference compounds chosen to include some of the structural features of aspirin and compare spectra and structures of the reference compounds to develop a correlation chart for chemical shifts. This process is done in small groups using shared class data and is guided by a series of questions designed to relate the different kinds of hydrogen atoms to number and position of peaks in the NMR spectrum. Students then identify the peaks in the NMR spectrum of their aspirin product and relate percent purity by titration with spectral results and percent yield. This is an enjoyable project that combines the synthesis of a familiar material with a guided inquiry-based introduction to NMR spectroscopy.

Varicella-zoster.

Varicella-zoster.

Reyes Syndrome

Reye's syndrome (RS) is a biphasic illness that occurs predominately in children and adolescents. A prodromal viral illness (frequently influenza A or B or chicken pox) is followed by protracted vomiting and neurologic changes that start 3 to 5 days later, just when the child seems to be recovering. Aspirin has been identified as one factor contributing to the metabolic disorder that occurs. Since 1986 the FDA has required labels on all aspirin products warning about the association of aspirin use and RS. Media messages heightened public awareness regarding the alternatives to aspirin for analgesia and antipyretic use. Since 1988, the incidence of RS has decreased dramatically. RS is now more prevalent in older adolescents who may self-medicate. Because early recognition of the disease is associated with decreased morbidity and mortality, it is important for health care providers to recognize the symptoms of RS. Unexpected vomiting and disturbed brain functioning following a viral illness are symptoms of RS in children and adolescents. In infants, the symptoms of RS may be more subtle, including diarrhea, respiratory disturbances, and seizures.

Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product

Aspirin products are known to cause irritation and injury to the gastric mucosa. The belief that enteric-coated and buffered varieties are less likely to occasion major upper-gastrointestinal bleeding (UGIB) than plain aspirin was tested in data from a multicentre case-control study. 550 incident cases of UGIB admitted to hospital with melaena or haematemesis and confirmed by endoscopy, and 1202 controls identified from population census lists, were interviewed about use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) during the 7 days before the onset of bleeding (cases) or interview (controls). Relative risks of UGIB for each type of aspirin used regularly (at least every other day) were calculated overall, and according to dose, by multiple logistic regression, with control for age, sex, marital status, date, education, cigarette smoking, alcohol use, and use of NSAIDs. The relative risks of UGIB for plain, enteric-coated, and buffered aspirin at average daily doses of 325 mg or less were 2.6, 2.7, and 3.1, respectively. At doses greater than 325 mg, the relative risk was 5.8 for plain and 7.0 for buffered aspirin; there were insufficient data to evaluate enteric-coated aspirin at this dose level. There were no important differences in risk attributable to the three aspirin forms according to bleeding site (gastric vs duodenal), or when users of NSAIDs were excluded. Use of low doses of enteric-coated or buffered aspirin carries a three-fold increase in the risk of major UGIB. The assumption that these formulations are less harmful than plain aspirin may be mistaken.

SHORT TAKES

When Bayer Corporation, the giant German chemical company, regained U.S. rights to its world famous Bayer aspirin product in 1994—rights it lost when its U.S. assets were confiscated by the government and sold to Sterling Pharmaceutical after World War I—it also regained the rights to the Bayer name for its U.S. operations. At a recent meeting of the Societe de Chimie Industrielle in New York, Helge H. Wehmeier, CEO of Bayer USA, told fellow chemical executives about the strategic importance of being Bayer again in the U.S.:

Accuracy of diagnostic procedures in acute upper gastrointestinal bleeding

Aspirin products are known to cause irritation and injury to the gastric mucosa. The belief that enteric-coated and buffered varieties are less likely to occasion major upper-gastrointestinal bleeding (UGIB) than plain aspirin was tested in data from a multicentre case-control study.550 incident cases of UGIB admitted to hospital with melaena or haematemesis and confirmed by endoscopy, and 1202 controls identified from population census lists, were interviewed about use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) during the 7 days before the onset of bleeding (cases) or interview (controls). Relative risks of UGIB for each type of aspirin used regularly (at least every other day) were calculated overall, and according to dose, by multiple logistic regression, with control for age, sex, marital status, date, education, cigarette smoking, alcohol use, and use of NSAIDs.The relative risks of UGIB for plain, enteric-coated, and buffered aspirin at average daily doses of 325 mg or less were 2·6, 2·7, and 3·1, respectively. At doses greater than 325 mg, the relative risk was 5·8 for plain and 7·0 for buffered aspirin; there were insufficient data to evaluate enteric-coated aspirin at this dose level. There were no important differences in risk attributable to the three aspirin forms according to bleeding site (gastric vs duodenal), or when users of NSAIDs were excluded.Use of low doses of enteric-coated or buffered aspirin carries a three-fold increase in the risk of major UGIB. The assumption that these formulations are less harmful than plain aspirin may be mistaken.

Suicide Attempt by Means of Aspirin Enema

To report a suicide attempt with an aspirin enema. A patient presented to the emergency room after self-administering, in enema form, approximately 700 aspirin tablets dissolved in water. Over the next 12 hours the patient became progressively acidemic with eventual cardiac arrest and subsequent chronic hypoxic encephalopathy. This patient's poor outcome was the result of retained aspirin products in the rectal vault combined with the failure to recognize the delayed absorption properties of rectally administered aspirin. In rectal aspirin overdoses, aspirin absorption from the rectum may occur over a long period of time. It is important to remove as much aspirin from the rectum as possible and to closely monitor these patients so that appropriate therapy may be started quickly. Activated charcoal given both in enema and oral form may help decrease aspirin absorption. Hemodialysis should be available and performed without delay should the patient require it.

In VitroDissolution VersusIn VivoEvaluation of Four Different Aspirin Products

The single dose pharmacokinetic characteristics of four aspirin formulations in humans were compared with their in vitro dissolution properties. The pharmacokinetic parameters were determined by measuring salicylate concentrations in the plasma. Dissolution was measured by using the USP XX single time point dissolution test. The four aspirin products were a commercial tablet, a commercial capsule, a capsule filled with a commercial granulation, and a slow dissolving capsule formulation that failed the USP dissolution specification. It was found that there was a poor correlation between the in vitro dissolution results and the in vivo computed pharmacokinetic parameter statistics. In vivo testing in humans showed that all of the formulations were bioequivalent in terms of half-life and AUC, and the capsule that failed to pass the dissolution specification was bioequivalent to two of the three products that did pass the specification with respect to the maximum plasma concentration. None of the products could be demonstrated to be bioequivalent with regard to the time to maximum plasma concentration. However, none of the in vivo differences between the four aspirin formulations were judged to be clinically significant. Therefore, while there was a poor relationship between the in vitro USP XX dissolution test results and the bioequivalence test results, from a practical viewpoint the dissolution test is a satisfactory manufacturing quality control test, since it can detect differences in in vitro dissolution prior to their having a significant clinical impact.

EPIDEMIOLOGIC ANTECEDENTS OF PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN

Despite the clinical and public health significance of Persistent Pulmonary Hypertension of the Newborn (PPHN), little is known about the syndrome's epidemiologic origins. Between July 1985 and April 1989 we interviewed a total of 103 mothers of case and 309 mothers of control infants who were hospitalized at two Harvard-affiliated neonatal intensive care units. A priori hypotheses focused on events linked to three potential pathophysiologic events: 1) inhibition of prostaglandin synthesis (i.e., maternal intake of aspirin and nonsteroidal anti-inflammatory agents [NSAIDs]), 2) fetal hypoxemia (i.e., maternal cigarette and marijuana smoking), and 3) vasospasm (i.e., maternal cocaine abuse). Two of our principal hypotheses were supported: odds ratios [OR] (95% confidence intervals [CI]) for the variables of greatest interest were: smoking=2.0 (1.2, 3.4), NSAIDs=3.6 (1.3, 10.3), aspirin products=2.1 (.89, 5.1), and illicit drugs=2.6 (.88, 7.7). Very low prevalence of confessed illicit drug use among our subjects precluded drug-specific analyses. We have tested a number of multivariate models using logistic regression to control for factors used as measures of socioeconomic status. In each model, maternal use of aspirin products and/or NSAIDs during pregnancy was linked with significantly increased risk of her infant developing PPHN, minimum OR (9 5%CI)=2,1 (1.3, 3.4). These data may have important implicat ions regarding future prevention of PPHN.

Effects of Professional and Media Warnings about the Association between Aspirin Use in Children and Reye's Syndrome

The media played a central role in changing the use of aspirin among children with viral illness following reports of its association with a rare but deadly disease, Reye's syndrome (RS). It did so by alerting health professionals and parents about ways to prevent RS in children. Indeed, by the time aspirin product labeling was required by the FDA in 1986, most of the decline in RS incidence had already occurred. In the past, media-only health education campaigns have been relatively unsuccessful in achieving long-term changes in complex health behaviors. This article supports the theory that media warnings about the hazards of common products may successfully change consumer behaviors when the illness is devastating, the behavioral message is simple, acceptable and inexpensive alternatives are available, and the campaign is comprehensive, involving multiple professional groups to reinforce direct appeals to consumers.

Biopharmaceutical evaluation of a tablet dosage form made from ethyl cellulose encapsulated aspirin particles

Ethyl cellulose encapsulated aspirin particles, suitable for preparation of direct compression tablets were prepared by the solvent evaporation method. Ethyl acetate was used as a solvent for the polymer in combination with a saturated solution of aspirin as the dispersing medium to prevent partitioning and drug loss. This resulted in a high yield of free-flowing, non-aggregated particles. In vitro-in vivo evaluations of the experimental aspirin tablets (made by direct compression of ethyl cellulose encapsulated particles) and three different commercial aspirin products (a conventional tablet, a timed-release tablet, and a timed-release caplet) were undertaken. Comparison of the dissolution in acidic media at pH 1.2 showed different release profiles for these products. While the conventional tablet and the timed-release caplet showed the highest and the lowest rate of release, respectively; the timed-release tablet and the experimentally made tablet revealed an intermediate rate and very similar release profiles. The cumulative urinary excretion data collected in a complete crossover study, using five healthy subjects further indicated that the experimental tablet has an in vivo availability identical to that of the timed-release tablet.

Effect of storage on tabletted microencapsulated aspirin granules

The antithrombotic effect of aspirin has been demonstrated through the use of small daily doses of the drug. Slow release formulations were shown to be adequate dosage form for this purpose. In this study, two sustained release formulations of aspirin were prepared and compared to plain aspirin tablets for their drug release and behavior upon storage at 40°C/90% relative humidity (R.H.). The polyacrylate-polymethacrylate based polymers were found suitable for the preparation of a sustained release aspirin product. The release characteristics of the drug were adequate to meet its antithrombotic effect. Storage-related changes observed in this study should help in better understanding and proper treatment of such formulations for the sake of obtaining more stable products with predictable uniform drug release.

The effect of aspirin on serum immunoglobulins.

After discontinuing aspirin products for seven days, 21 aspirin tolerant adults were given 650 mg of aspirin daily for one week. Serum immunoglobulins (IgG, IgA, IgM, and IgE), complete blood count (CBC), and total eosinophil counts (TEC) were determined before aspirin challenge, four hours after initial challenge, on day seven of aspirin ingestion, 24 hours after discontinuing aspirin, and three weeks after discontinuing aspirin. No significant changes were noted in any of these categories. Although aspirin is an anti-inflammatory drug similar to corticosteroids, it does not produce immunological changes that corticosteroids produce as determined by these parameters.

Minimization of salicylic acid formation during preparation of aspirin products for analysis by high-performance liquid chromatography.

The simultaneous separation of aspirin and its degradation product salicylic acid, together with caffeine and paracetamol, can be achieved by reversed-phase high-performance liquid chromatography. The accuracy of measurement of salicylic acid is reduced by conversion of aspirin into salicylic acid during sample preparation. This is a serious limitation when other components of aspirin preparations, such as carbonates, catalyse the conversion or when sample solutions are prepared in advance for use with an autoinjector. A sample solvent containing acetic anhydride, oxalic acid and acetic acid has been found to reduce hydrolysis to about 5% of that of a conventional solvent (methanol).

Aspirin products must carry warning label

Aspirin products must carry warning label

WHICH ASPIRIN PRODUCT?

WHICH ASPIRIN PRODUCT?

Aspirin—a national survey I: Semiautomated determination of aspirin in bulk and tablet formulations and salicylic acid in tablet formulations

A semiautomated assay to determine aspirin (acetylsalicylic acid) in aspirin tablets, powdered tablet composites, and pure drug substances is presented. The sample was dissolved in alcoholic buffer, diluted, and extracted with chloroform. The absorbance of the chloroform solution was read at 280nm. Results obtained by the USP XIX and semiautomated methods are compared. The proposed method is accurate and precise, and common excipients do not interfere. Recoveries of 100% were obtained. A semiautomated assay for salicylic acid in aspirin tablets also is presented. The sample was dissolved in alcoholic buffer, ferric nitrate was added, and the absorbance of the resulting purple color was read at 532nm. The method is suitable as a rapid screening procedure for testing the salicylic acid content of aspirin products. Results obtained by the USP XIX and semiautomated methods are compared, and the accuracy and precision of the proposed method are given. One hundred seventy tablet samples and 34 bulk drug substances were analyzed for aspirin and salicylic acid content. Approximately 5% of the tablet samples failed to meet the USP XIX limits for aspirin content, and 10% failed to meet the limits for salicylic acid.

Comparative Bioavailability of Enteric-Coated Aspirin Preparations

A three-way crossover study was conducted in nine healthy subjects to compare the bioavailability of one uncoated and two enteric-coated aspirin products after the administration of a single 650-mg dose of each preparation. Urine was collected at various intervals for 24 hours after drug administration and assayed for total salicylic acid content as an indicator of bioavailability. There were statistically significant differences among the three products in the amount of salicylic acid appearing in the urine, both for specific collection intervals and for cumulative (24-hour) excretions. Greater (p < 0.001) amounts of urinary salicylic acid were found in the first three hours after uncoated aspirin treatment than after enteric-coated aspirin administration. After 24 hours, equivalent amounts of salicylic acid were found following treatment with uncoated aspirin and one of the enteric-coated preparations. The absorption of aspirin from enteric-coated preparations is markedly delayed when compared to that from an uncoated product.

Effect of Safety Packaging on Aspirin Ingestion by Children

The effectiveness of child-resistant closures, required under the Poison Prevention Packaging Act of 1970, in reducing the incidence of accidental ingestion of aspirin and aspirin-containing products among children less than 5 years of age has been investigated. Data from Poison Control Centers and the National Center for Health Statistics were analyzed to determine the ingestion level before and two to three years after safety closures were required. Baby aspirin and nonbaby aspirin products were analyzed separately. For baby aspirin. It is estimated that safety packaging has reduced the incidence of ingestions 45% to 55%. For nonbaby aspirin products, the reduction has been 40% to 45%.