Influence of raw material properties upon critical quality attributes of continuously produced granules and tablets.

Continuous manufacturing gains more and more interest within the pharmaceutical industry. The International Conference of Harmonisation (ICH) states in its Q8 'Pharmaceutical Development' guideline that the manufacturer of pharmaceuticals should have an enhanced knowledge of the product performance over a range of raw material attributes, manufacturing process options and process parameters. This fits further into the Process Analytical Technology (PAT) and Quality by Design (QbD) framework. The present study evaluates the effect of variation in critical raw material properties on the critical quality attributes of granules and tablets, produced by a continuous from-powder-to-tablet wet granulation line. The granulation process parameters were kept constant to examine the differences in the end product quality caused by the variability of the raw materials properties only. Theophylline-Lactose-PVP (30-67.5-2.5%) was used as model formulation. Seven different grades of theophylline were granulated. Afterward, the obtained granules were tableted. Both the characteristics of granules and tablets were determined. The results show that differences in raw material properties both affect their processability and several critical quality attributes of the resulting granules and tablets.

3D simulation of internal tablet strength during tableting.

This study presents a new approach to model powder compression during tableting. The purpose of this study is to introduce a new discrete element simulation model for particle-particle bond formation during tablet compression. This model served as the basis for calculating tablet strength distribution during a compression cycle. Simulated results were compared with real tablets compressed from microcrystalline cellulose/theophylline pellets with various compression forces. Simulated and experimental compression forces increased similarly. Tablet-breaking forces increased with the calculated strengths obtained from the simulations. The calculated bond strength distribution inside the tablets showed features similar to those of the density and pressure distributions in the literature. However, the bond strength distributions at the center of the tablets varied considerably between individual tablets.

Accelerated dissolution testing for controlled release microspheres using the flow-through dissolution apparatus.

Theophylline controlled release capsules (THEO-24 CR) were used as a model system to evaluate accelerated dissolution tests for process and quality control and formulation development of controlled release formulations. Dissolution test acceleration was provided by increasing temperature, pH, flow rate, or adding surfactant. Electron microscope studies on the theophylline microspheres subsequent to each experiment showed that at pH values of 6.6 and 7.6 the microspheres remained intact, but at pH 8.6 they showed deterioration. As temperature was increased from 37-57 degrees C, no change in microsphere integrity was noted. Increased flow rate also showed no detrimental effect on integrity. The effect of increased temperature was determined to be the statistically significant variable.

Determination of glucosamine in horse plasma by liquid chromatography tandem mass spectrometry.

Glucosamine is an amino sugar involved in the biosynthesis of glycosylated proteins and lipids. Recently, with increased public interest in natural products medicine, glucosamine has been widely used to treat osteoarthritis, even though demonstrations of its actual efficacy remain relatively unknown. Information related to the pharmcokinetics of glucosamine is sparse. A recent analytical method published used 13C-glucosamine as an internal standard to analyse study samples. The method lacked accuracy owing to an important natural isotopic contribution of glucosamine to 13C-glucosamine ion abundance. This manuscript describes a simple method to quantify glucosamine in horse plasma. Glucosamine was extracted by protein precipitation with acetonotrile containing 0.1% formic acid. The chromatography was performed on a Agilent Hypersil-ODS 100x2.1 mm column with a mobile phase composed of acetonitrile and 0.5% formic acid in water (45:55) at a flow rate of 0.3 mL/min. A linear (1/x) relationship was used to perform the calibration over an analytical range of 10-1000 ng/mL. The inter-batch precision and accuracy ranged from 5.3 to 11.3% and from 87.8 to 107.2% in horse plasma, respectively. The mean endogenous level of glucosamine in horse plasma was 14.4 ng/mL (n=6). This LC-ESI/MS/MS method for the determination of glucosamine in horse plasma provided results within generally accepted criteria used for bioanalytical assay.

[Current problems in the quality control of pharmaceutical preparations manufactured in pharmacies III. Investigation of theophilline containing suppositories]. / Magisztrális gyógyszerkészítmények minoségellenorzésének aktuális kérdései III. Teofillin tartalmú kúpok vizsgálata.

In the present part of our series of papers a study on theophilline containing suppositories prepared in pharmacies is described. From the possible methods for assay of theophilline two nonaqueous titrations are compared. In first, theophilline is measured as a very weak base in a mixture of glacial acetic acid and acetic anhydride with perchloric acid using Sudan-III indicator, in second, the compound is measured as medium strong acid in dimethylformamide solvent with sodium-hydroxide titrant using phenolphtalein indicator. These methods were validated and the first was found more appropriate for regulatory control. We investigated suppositories prepared in our laboratory and in different pharmacies. The study revealed the poor quality of the preparations due to the difficulties in the technology and the importance of the applied vehicle. A guideline for the good preparation practice and an alternative technology are proposed.

Assessment of CYP1A2 activity in clinical practice: why, how, and when?

The cytochrome P450 enzyme CYP1A2 mediates the rate-limiting step in the metabolism of many drugs including theophylline, clozapine, and tacrine as well as in the bioactivation of procarcinogens. CYP1A2 activity shows both pronounced intra- and interindividual variability, which is, among other factors, related to smoking causing enzyme induction, to drug intake and to dietary factors which may result in induction or inhibition. In contrast to these exogenous factors, genetic influences on enzyme activity seem to be less pronounced. Therefore, phenotyping of CYP1A2, i.e. the determination of the actual activity of the enzyme in vivo, represents a useful approach both for scientific and clinical applications. CYP1A2 is almost exclusively expressed in the liver. Since liver tissue cannot be obtained for direct phenotyping, a probe drug which is metabolized by CYP1A2 has to be given. Proposed probe drugs include caffeine, theophylline, and melatonin. Caffeine is most often used because of the predominating role of CYP1A2 in its overall metabolism and the excellent tolerability. Various urinary, plasma, saliva, and breath based CYP1A2 caffeine metrics have been applied. While caffeine clearance is considered as the gold standard, the salivary or plasma ratio of paraxanthine to caffeine in a sample taken approximately 6 hr after a defined dose of caffeine is a more convenient, less expensive but also fully validated CYP1A2 phenotyping metric. CYP1A2 phenotyping is applied frequently in epidemiologic and drug-drug interaction studies, but its clinical use and usefulness remains to be established.

Theophylline revisited.

Theophylline was first isolated in 1888 and remains the most commonly used medication worldwide for the treatment of asthma. It decreases the need for asthma rescue medications by people who have asthma and is an effective steroid-sparing agent for patients who tolerate it. Recently, investigators have shown that theophylline decreases airway inflammation, accelerates eosinophil apoptosis, and decreases recruitment of lymphocytes and neutrophils to the lungs at low doses. It is classified as a phosphodiesterase (PDE) inhibitor, but its therapeutic mechanism of action remains undetermined. Theophylline should be reevaluated as a long-term medication for the treatment of asthma because of its ease of use, low cost, and recent evidence of its anti-inflammatory actions.

[Requirements for product quality of theophylline sustained-release preparations]. / Anforderungen an die Produktqualität von Theophyllin-Retardpräparaten.

In consideration of the narrow therapeutic range and the pharmacology of theophylline (CAS 58-55-9), the pharmaceutic quality of sustained release theophylline preparations should be monitored carefully. During the last few years, the following pharmacokinetic study programme was established as quality criterion to verify the safety and predictability of theophylline concentration-time profiles: bioequivalence from batch to batch, lack of relevant food interaction, lack of relevant gastrointestinal pH or surfactant effects on absorption, pharmacokinetic profile following once-a-day and twice-a-day application, and pharmacokinetics in high-clearance patients. Smooth, predictable and safe concentration-time profiles can be guaranteed exclusively for preparations which fulfill all these quality criteria. Only such high quality formulations allow to reduce or even avoid therapeutic drug monitoring and can be considered as safe and effective drugs for the chronic treatment of asthma.

Control serum for therapeutic drug monitoring.

New control material EXAPHARM (IMUNA s.p., Sarisské Michalany, Slovakia) for therapeutic drug monitoring (TDM) was evaluated. It is produced in two types: Exapharm AED containing 6 antiepileptic drugs and Exapharm CARD with 4 cardiac and antiasthmatic drugs. Both contain horse serum as a matrix, which is different in some parameters from human serum. Our results approved an outstanding stability and inter-bottle homogeneity of the material. Evidence was presented that no interferences occur in high performance liquid chromatography (HPLC) under the conditions described. It is concluded, that this control serum is very suitable for TDM by HPLC.

[Studies on the identification of psychotropic substances. VIII. Preparation and various analytical data of reference standard of some stimulants, amfepramone, cathinone, N-ethylamphetamine, fenethylline, fenproporex and mefenorex].

The Reference Standards for amfepramone, cathinone, N-ethylamphetamine, fenethylline, fenproporex and mefenorex were prepared. Their purities determined by HPLC were more than 99.5%. For the identification and determination of these six drugs, their analytical data were measured and discussed by TLC, UV, IR, HPLC, GC/MS and NMR.

Repeated dosing of Uniphyl tablets under fed and fasting conditions: comparison of serum theophylline levels, pulmonary function, and asthma symptoms.

In order to determine the effects of repeated administration under fed and fasting conditions on the bioavailability and clinical efficacy of Uniphyl tablets, 22 adult asthmatics took the drug immediately following their evening meal for seven consecutive days and under fasting conditions for an additional seven consecutive days. For each patient, the daily theophylline dose remained constant throughout the study. Peak and trough serum theophylline concentrations (STC), spirometry, asthma symptoms, side effects and use of beta-agonist inhalers were recorded daily at 0730 and 1900 hours. The mean daily theophylline dose was 818.2 +/- 213.0 mg. The mean peak STC when Uniphyl was taken with food was 14.4 +/- 4.5 mg/L and was 13.1 +/- 3.6 mg/L when taken under fasting conditions (P less than .05). The trough STC was 7.4 +/- 2.8 mg/L with food and 6.9 +/- 2.1 mg/L while fasting (NS). There were no significant differences between the two dosing conditions in terms of spirometry, asthma symptom scores, side effects or use of beta-agonist inhalers. There was no significant difference between the patients' morning and evening FEV1 under either dosing condition. Since the differences in STC between fed and fasting conditions were not clinically significant, we conclude that there is no need to restrict patients to a rigid relationship between Uniphyl dosing and meal conditions. On the basis of patient preference and compatibility with a normal lifestyle, we recommend that patients should generally be instructed to take the drug with or shortly following their evening meal.

Accuracy and precision of methods for theophylline measurement in physicians' offices.

We tested the accuracy and precision of five theophylline methods intended for use in physicians' offices. The Syntex AccuLevel, Ames Seralyzer, and 3M Diagnostics TheoFAST methods were less reproducible (CVs 6.3% to 9.2%) than the Abbott Vision and Kodak DT-60 (CVs 2.2% to 3.3%). Caffeine interfered with the Vision, Seralyzer, and AccuLevel methods, and theobromine interfered with the Vision, Seralyzer, and TheoFAST methods. Only the DT-60 method was free from interference from any of the 24 compounds tested. Results by all methods correlated well with those by the HPLC comparison method (Clin Chem 1981;27:1931-3) and by the Abbott TDx method for assay of 100 serum (or, when appropriate, paired whole-blood) samples. The frequency of sample results differing from the comparison method by greater than 2.0 mg/L was as follows: TDx, 11%; Vision (serum), 12%; Vision (whole blood), 18%; DT-60, 14%; AccuLevel, 18%; Seralyzer, 25%; and TheoFAST, 31%. The Kodak DT-60 method was the most nearly accurate and precise among these physician's office methods. Some physician's office methods for theophylline analysis are not adequate to guide dosage adjustments.

Inadequacy of FDA dosing guidelines for intravenous theophylline.

The ability of a dosing regimen of intravenous theophylline to achieve therapeutic serum theophylline concentrations was evaluated. Intravenous theophylline was administered to 25 adult patients with acute bronchospasm using dosing guidelines 20 percent higher than FDA recommendations. The dose of theophylline was determined by assignment to one of four clinical categories. Blood samples for determination of serum theophylline concentrations were collected 12 and 24 hours after initiation of a constant infusion. Differences between mean observed and target theophylline concentrations did not achieve statistical significance. All patients in categories 1 and 2 achieved therapeutic concentrations of theophylline. Most of those with subtherapeutic levels were smokers suffering from multiple diseases. We conclude that current FDA recommendations for dosing intravenous theophylline are unreliable for routine use in category 3 and 4 patients. Further work is necessary to evaluate these recommendations in pediatric and category 1 and 2 patients.

The reliability of serum theophylline determinations from clinical laboratories.

Three aliquots of pooled serum containing theophylline and disguised as patient specimens were sent, one at a time, on different days, to 29 community hospital and referral laboratories serving Iowa. The mean +/- SEM concentration of 65 replications for the same serum pool was 15.7 +/- 0.1 microgram/ml. Twenty-eight per cent of the 85 measurements reported by the clinical laboratories were outside the acceptable range of 13.2 to 18.1 microgram/ml established by the 95% confidence limits of the assayed pool. Reliability of the results was not related to the type of facility, method of measurement, or fee charged. Therefore, variation in clinical laboratory performance was a result of technician error in handling or analyzing the specimens. We conclude that measurements of serum theophylline can only be relied on to adjust dosage when the accuracy of the laboratory has been established with blinded samples.

Improved theophylline serum analysis by an appropriate internal standard for gas chromatography.

A gas chromatographic method is presented for the measurement of theophylline in serum. To serum samples containing the drug the internal standard, 3-isobutyl-l-methylxanthine, was added and the serum was saturated with ammonium carbonate. A mixture of isopropanol-chloroform (5:95) was used for extraction. The organic phase was filtered and evaporated. The residue, dissolved in chloroform, was extracted with sodium hydroxide. The basic solution was acidified, washed with hexane and reextracted with isopropanol-chloroform. The organic phase was dried with anhydrous sodium sulphate before evaporation. The sample was derivatized with n-Butyl-8 reagent. 85% of theophylline was recovered by extraction. 3-Isobutyl-l-methylxanthine was recovered with the same efficiency as theophylline and gas chromatographed well. The standard curve was linear between 1.0 and 50.0 mug/ml theophylline. No interference was encountered from normal serum constituents or methylxanthines such as caffeine, theobromine, or 3-methylxanthine. Serum samples were stared in the refrigerator for two weeks without significant loss of drug. The precision and accuracy of the method were good.