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The construction and uses of factorial designs in the preparation of solid dosage forms. Part 1: Effervescent acetylsalicylic acid tablets.

The construction and application of a fractional factorial design of the type N = 2(5-2) for the preparation of effervescent acetylsalicylic acid tablets by a new technique was demonstrated. This method involved direct compression of the tablet ingredients, dipping the tablets in a volatile mixed solvent system and subsequent removal of the solvent. With the help of a derived regression equation, the factors considered most likely to have a beneficial effect on tablet hardness were: the compression force, the percent of acetylsalicylic acid content/tablet, the particle size of tablet ingredients and the solvent ratio. The time of dipping was found to have an insignificant effect on tablet hardness. By following the path of the steepest ascent, effervescent acetylsalicylic acid tablets of remarkable hardness, friability and dissolution time were obtained. The optimum conditions for preparing these tablets were determined.

Aspirin↗

Pharmacological basis of dosage form of two antimalarials: chloroquine and mepacrine.

Chloroquine and mepacrine appear in the stomach wall and inhibit gastric emptying in the rat after oral or parenteral administration. Measuring their concentration in the stomach wall, it was found that it depended upon on the route of application. A smaller proportion of a given dose accumulated in the stomach wall when chloroquine and mepacrine were introduced by avoiding the stomach. The side effect of the two drugs, the inhibition of gastric motility, could be minimized by not only parenteral but also duodenal administration; the latter could be realized by enteric-coated tablets.

Administration, Oral↗

The construction and uses of factorial designs in the preparation of solid dosage forms. Part 3. Effect of temperature and time on the mechanical properties of sintered tablets.

The present and forecoming series of experiments illustrate the application of factorial design to the study of the sintering phenomena of pharmaceutical tablets. This part was concerned with the effect of temperature (X1) and time (X2) on the mechanical properties of sintered tablets. A 2 X 2 design was developed for salicylamide tablets with the two factors at two levels, and a 3 X 3 design for phenobarbital tablets with the two factors at three levels. Analysis of variance was used to determine the significant effects. Empirical regression equations were obtained which indicated that the hardness of sintered tablets was markedly improved by using the high level of X1 at the low level of X2 in phenobarbital tablets, and the high levels of both X1 and X2 in salicylamide tablets. The tablets tensile strength was a linear function of X1 and X2, but the interaction effect X1X2 was insignificant. Significant quadratic effects of X2/2 and/or X2/1 were also detected for the mechanical properties of phenobarbital tablets.

Drug Compounding↗

The construction and uses of factorial designs in the preparation of solid dosage forms.

The present experiments were factorially designed to study the effect of particle size (X3), at different levels of both temperature (X1) and time (X2), on the hardness and mechanical strength of sintered tablets. A 2 X 2 X 3 design was constructed for salicylamide tablets with X1, X2 and X3 at 2,2 and 3 levels respectively. For phenobarbital tablets, a 3 X 3 X 3 factorial experiment was run. On the basis of analysis of variance, empirical regression equations have been developed. Within the limits of the factors, it was found that the quadratic effect of X 2/3, on the average, was the most significant. The significance of the linear effects was in the following order: X3 greater than X1 greater than X2 in salicylamide tablets and X1 greater than X3 greater than X2 in phenobarbital tablets. A change of X3 from the high to the low or intermediate levels caused an increase in the mechanical properties of tablets. The only linear interaction was that of X1X3 for the hardness data of phenobarbital tablets, but it was of least significance among the other effects. Other quadratic main effects of X 2/1, X 2/2 and quadratic interaction effects of X 2/3X1 and X 2/1X2 were also found to be significant. The optimum values of the factors studied, that would maximize any given mechanical property, were located.

Drug Compounding↗

Spectrophotometric investigation of metoprolol-benzyl orange reaction and its application to the assay in pharmaceutical dosage forms.

A sensitive spectrophotometric method for the determination of metoprolol tartrate in tablets and ampoules is presented. Using spectrophotometric measurements, it was found that metoprolol tartrate and benzyl orange form a chloroform soluble ion-pair complex with an absorption maximum at 401 nm. The composition of the ion-pair complex was determined by applying Job's method to equimolar solutions of metoprolol tartrate: benzyl orange (1:2); molar absorptivity 7.39 x 10(3) mol-1 cm-1. Extraction of the ion-pair complex in chloroform was accomplished easily at a Britton-Robinson's buffered optimum pH = 5.2, mu = 0.1 mol/dm3. The relative stability constant, calculated according to the method of Sommer and Job's non-equimolar solutions, was log K = 9.72 (avg. value). Beer's law was obeyed up to 3.42 micrograms/ml of metoprolol tartrate (the detection limit was also 3.42 micrograms/ml). The precision of the method was checked at three different concentrations. The RSD (n = 7) varied from 0.51 to 2.03%. Reproducibility was examined by analysing Lopresor tablets and ampoules. Recoveries varied from 99-101%. The reported method, applied to the assay of metoprolol tartrate in tablets and ampoules, gives precise and reproducible results.

Azo Compounds↗

[Comparison between 2 steroid dosage forms in psoriasis and eczema].

This trial was designed to evaluate the clinical effect of a new Topical steroid, the desoximetasone (test name A 41 304 from Hoechst Aktiengesellschaft). A randomized, double-blind, right-left comparative trial has been carried out in 22 patients with atopic dermatitis and on 24 patients with psoriasis. As a comparative drug, a betamethasone 17-valerate preparation, being the strongest on the market, has been used. The new compound showed a better effect on both indications, the difference being significant (p less than 0,005) on psoriasis.

Adolescent↗

[FDDF (fast dissolving dosage form) piroxicam for sublingual administration in the treatment of rheumatoid arthritis].

Open non-comparative study for the evaluation of the efficacy and tolerance of piroxicam FDDF for sublingual administration in the treatment of rheumatoid arthritis. Thirty patients (6 males and 24 females) suffering from rheumatoid arthritis in the active phase have been treated. All the patients had to fulfil the criteria for the rheumatoid arthritis classification proposed by the American Rheumatism Association (ARA). The efficacy of therapy has been evaluated, after 2, 4 and 6 week of treatment, through the changes in: the number of painful or tender joints on motion, the number of swollen joints, grip strength, ESR. Also day pain, night pain, duration of morning stiffness and functional index have been evaluated. As regards the functional index, activities as dressing, arising, eating, walking, taking care of hygiene, bending, standing and sitting have been considered. The study sample was composed by 30 patients, with a mean age of 59.73 years, suffering from rheumatoid arthritis from 4.76 years. As regards efficacy parameters, day pain, which is recorded on a 21 compartment visual analogue scale, was initially of 8.13 (+/- 3.73), and after 2 weeks of therapy decreased of about 1 point and after 4 weeks was of 6.57 (+/- 3.73). This improvement was already statistically significant at the first control (p = 0.01). At the first control also morning stiffness resulted improved in a statistically significant way (p < 0.0001). As regards functional index a statistically significant improvement was observed in the disability of walking and of picking up objects after 2 weeks; after 4 weeks a significant improvement was observed in the disability of arising and of bending. These changes in functional ability probably depend upon the kind of joint involved and the duration of these lesions. Also the grip strength resulted statistically improved at the 2 control. As regards objective values, there was a statistically significant improvement in tender and swollen joints after only 2 weeks. As regards ESR, which is an index of disease activity, was initially of 40.73 (+/- 16.75) in mean; at the end of the 6th week it was of 34.72 (+/- 15.13): this reduction was statistically significant. No improvement was observed in night pain, normally the pain form which is more difficult to cure. As regards toleration, only 2 patients reported side-effects: the first reported epigastralgia and the second oral burning Both side-effects lasted 1 day and, according to the physician, their relation with the study drug is not sure.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Sublingual↗