Statistical Comparison of the Dissolution curves of Controlled-Release Solid Oral Dosage Forms

Abstract

This paper shows how the Box method, based on the statistical technique known as “split-plot” in general use for replicate measurements, may be used to quantify and compare in vitro dissolution curves of controlled release solid oral dosage forms. In this case, it is applied to the interpretation of the findings of a stability test on controlled-released lithium tablets formulated with a wax matrix and containing 10.8 mEq lithium per tablet. The findings showed that the total amount of lithium dissolved after the tablets had been stored for a period of six months was slightly greater than before storage; the dissolution mean rate went from 1.06 mEq/h to 1.17 mEq/h and the dissolution rate curve profile apparently registered less variation.

The method described here for the comparison of dissolution curves is particularly useful when the curves do not follow a set kinetic process and has proved sensitive to slight changes in the dissolution profile.     

Statistical Comparison of the Dissolution curves of Controlled-Release Solid Oral Dosage Forms

This paper shows how the Box method, based on the statistical technique known as “split-plot” in general use for replicate measurements, may be used to quantify and compare in vitro dissolution curves of controlled release solid oral dosage forms. In this case, it is applied to the interpretation of the findings of a stability test on controlled-released lithium tablets formulated with a wax matrix and containing 10.8 mEq lithium per tablet. The findings showed that the total amount of lithium dissolved after the tablets had been stored for a period of six months was slightly greater than before storage; the dissolution mean rate went from 1.06 mEq/h to 1.17 mEq/h and the dissolution rate curve profile apparently registered less variation.

The method described here for the comparison of dissolution curves is particularly useful when the curves do not follow a set kinetic process and has proved sensitive to slight changes in the dissolution profile.     

Oral Dosage Forms with Controlled Gastrointestinal Transit

Abstract

The present investigation concerns the development of new dosage forms which, after oral administration, exert an active influence on their gastrointestinal transit. The dosage forms release excipients which aim to increase the lenght of time the drug spends in the absorbing section of the duodenum and small intestine. A delayed gastrointestinal transit is intended to achieve a more complete and longer lasting absorption of drugs with a limited duration of absorption. The present study examined whether, by incorporating triethanolamine myristate (165 mg) as an excipient in tablets containing riboflavine (20 mg) as an example of a drug with limited absorption, the gastrointestinal transit of riboflavine could be delayed and hence its absorption improved. Five subjects took part in the in vivo studies and a pH-telemetering device (Heidelberg capsule) was used to determine gastric residence time.

The investigations showed that in 4 out of 5 subjects, the gastric residence time of the pH-telemetering capsule could be prolonged and the renal elimination of riboflavine increased The increase in renal elimination of riboflavine in the presence of triethanolamine myristate was statistically significant in the 4th urine collection period (0.05 > p> 0.0025).     

Dissolution Profiling of Six Modified-Release Oral Solid Dosage Forms

Abstract

Dissolution testing was conducted for six non-combination, single entity, modified-release oral solid dosage forms. Dissolution medium was water and 0.1 N hydrochloric acid. USP Apparatus 1 and Apparatus 2 were used arid were rotated at either 50 or 100 rpm. A complete dissolution profile was obtained for all six dosage forms based on their stated dosing interval, D. The three strengths of Theo-dur tablets, Norpace CR 150 mg capsules, and the two strengths of Chlor-trimeton tablets passed the Compendial Case One requirements (USP XXI, 2S, 1906). Thorazine spansules and Quinidex tablets were unable to meet the specifications with water as the dissolution medium; the latter showed improved dissolution character in 0.1 N hydrochloric acid. Tenuate Dospan 75 mg tablets showed good release characteristics in water when the authentic (dosing interval (D = 24 hours) was changed to a modified dosing interval of D* = 12 hours. All dissolution aliquots were assayed by UV absorbance measurements at the absorbance maximum for each drug and were also checked for excipient interference. Newer drugs appearing on the market will be more likely candidates for meeting compendial specifications; modified-release pharmaceuticals that appeared before the new specifications may have to be allocated specifically expanded window percentages.     

Dissolution of Omeprazole from Delayed-Release Solid Oral Dosage Forms

The evaluation of the biopharmaceutical quality of omeprazole enteric-coated products (granules in capsules) with respect to its dissolution characteristics is not specifically regulated in any of the most common official pharmacopoeia. USP 23 includes a general monograph for enteric-coated products. This paper reports the evaluation of the medium pH effect on the dissolution rates of omeprazole from four omeprazole-containing products of different manufacturers. It is concluded that the USP 23 recommended dissolution procedure for enteric-coated products is not suitable due to the degradation of omeprazole under such conditions. Furthermore, the medium with pH 8.0 showed different dissolution rates not observed at pH 7.4, allowing discrimination between products of different manufacturers.     

Dissolution Profiling of Six Modified-Release Oral Solid Dosage Forms

Dissolution testing was conducted for six non-combination, single entity, modified-release oral solid dosage forms. Dissolution medium was water and 0.1 N hydrochloric acid. USP Apparatus 1 and Apparatus 2 were used arid were rotated at either 50 or 100 rpm. A complete dissolution profile was obtained for all six dosage forms based on their stated dosing interval, D. The three strengths of Theo-dur tablets, Norpace CR 150 mg capsules, and the two strengths of Chlor-trimeton tablets passed the Compendial Case One requirements (USP XXI, 2S, 1906). Thorazine spansules and Quinidex tablets were unable to meet the specifications with water as the dissolution medium; the latter showed improved dissolution character in 0.1 N hydrochloric acid. Tenuate Dospan 75 mg tablets showed good release characteristics in water when the authentic (dosing interval (D = 24 hours) was changed to a modified dosing interval of D* = 12 hours. All dissolution aliquots were assayed by UV absorbance measurements at the absorbance maximum for each drug and were also checked for excipient interference. Newer drugs appearing on the market will be more likely candidates for meeting compendial specifications; modified-release pharmaceuticals that appeared before the new specifications may have to be allocated specifically expanded window percentages.     

Sensory Analysis of Liquid Oral Dosage Forms Antacid Suspensions

Sensory analysis of pharmaceutical oral dosage forms can be used effectively in product development and quality control to improve patient acceptance of the drug. In this work, sensory analysis is applied to detect consumer preference for formulations of aluminum and magnesium hydroxide antacid suspensions. A ranking test was applied to six peppermint flavored commercial samples (identified from A to F) of the antacid with the same therapeutical potency. The samples corresponded to four different formulations and six batches from three manufacturers. The ranking test was applied in duplicate to ten judges (ages 20–34) trained in the method and in the main sensory characteristics of the product. The coded samples were presented randomly in duplicate to each judge with six replications, and results were recorded in a preference scale from 1 to 6 (1 = most preferred). Statistical analysis of the data considered the sample as the only cause for variation and the minimum significant difference was determined at confidence levels of α = 0.01 and α = 0.05. The results show a highly significant preference (α = 0.01) in sample F over A, B, D and E. At α = 0.05, sample F was preferred over all the others, whereas formulations A and D were the least preferred at both significance levels. These results demonstrate that sensory analysis can be applied succesfully in product selection for the patient, formulation development and as a quality control tool in antacid suspensions.     

Comparative pH-Gradient Dissolution of Several Oral Dosage Forms of Iron

Abstract

A comparative pH - gradient dissolution study was conducted for several brands of oral iron dosage forms on the Canadian market. The commercially available dissolution apparatus employed in the study met the requirements of the variety of pH media conditions necessary for conducting dissolution of conventional, enteric coated and slow release iron preparations. The reproducibility of the dissolution system was evaluated using the USP's non-disintegrating salicylic acid tablets. Dissolution results are discussed in reference to a recent bioavailability report concerning oral iron preparations. The applicability of the procedure in studying the dissolution of solid dosage forms of iron is discussed.     

Comparative pH-Gradient Dissolution of Several Oral Dosage Forms of Iron

A comparative pH - gradient dissolution study was conducted for several brands of oral iron dosage forms on the Canadian market. The commercially available dissolution apparatus employed in the study met the requirements of the variety of pH media conditions necessary for conducting dissolution of conventional, enteric coated and slow release iron preparations. The reproducibility of the dissolution system was evaluated using the USP's non-disintegrating salicylic acid tablets. Dissolution results are discussed in reference to a recent bioavailability report concerning oral iron preparations. The applicability of the procedure in studying the dissolution of solid dosage forms of iron is discussed.     

Ketorolac Tromethamine Bioavailability Via Tablet, Capsule, and Oral Solution Dosage Forms

The single-dose mean pharmacokinetic characteristics and relative bioavailability of 10-mg ketorolac tromethamine tablet, capsule, and oral solution dosage forms were evaluated in 12 healthy volunteers in a randomized study of Latin square design. The tablet and the capsule formulations used were shown to have similar in vitro dissolution profiles. Ketorolac tromethamine was rapidly absorbed from all three dosage forms. The tablet and capsule were not significantly different with respect to any of the mean pharmacokinetic parameters: time to maximum plasma concentration (T_max) (35 and 42 min for the tablet and capsule, respectively), peak plasma concentration (C_max) (0.865 and 0.809 μg/ml for the tablet and capsule, respectively), area under the curve (AUC) (3.50 and 3.43 μg/ml × hr for the tablet and capsule, respectively), and half-life (t1/2) (5.2 and 4.8 hr for the tablet and capsule, respectively). Ninety-five percent fiducial (confidence) limits supported the equivalence of all of the tablet and capsule pharmacokinetic characteristics except for T^max, because of the higher variability of this parameter. The solution was absorbed significantly faster than the tablet (the time to maximum plasma concentration was 23 min for the solution versus 35 min for the tablet), but was not significantly different from the tablet in any other pharmacokinetic aspect. The fiducial intervals supported these tablet versus solution findings. Therefore, when functional or anatomical abnormality make tablet administration inadvisable, the solution or capsule formulations employed in this study may be used as alternatives to the commercially marketed tablet without adversely impacting the absorption profile of the drug substance.     

Oral Controlled-Release Dosage Forms. I. Cellulose Ether Polymers in Hydrophilic Matrices

An appropriately designed controlled-release drug delivery system can be a major advance towarb solving problems concerning the targeting of a drug to a specific organ or tissue and controlling the rate of drug delivery to the target tissue. Hydrophilic matrices are an interesting option when developing an oral controlled-release formulation. The present study focuses on oral controlled-release dosage forms and the application of cellulose ether polymers in hydrophilic matrices. Key Words. Controlled-release matrices; Hydrophilic matrices; Cellulose ether polymers; Hydroxypropylmethylcellulose; HPMC     

Oral Controlled-Release Dosage Forms. I. Cellulose Ether Polymers in Hydrophilic Matrices

Abstract

An appropriately designed controlled-release drug delivery system can be a major advance towarb solving problems concerning the targeting of a drug to a specific organ or tissue and controlling the rate of drug delivery to the target tissue. Hydrophilic matrices are an interesting option when developing an oral controlled-release formulation. The present study focuses on oral controlled-release dosage forms and the application of cellulose ether polymers in hydrophilic matrices. Key Words. Controlled-release matrices; Hydrophilic matrices; Cellulose ether polymers; Hydroxypropylmethylcellulose; HPMC     

Evaluation of an in Vitro Dissolution and Permeation Apparatus for Oral Solid Pharmaceutical Dosage Forms

An apparatus based in the USP dissolution test, the F-C-SL apparatus (Ferreira-Costa-Sousa Lobo), was developed that allowed the simultaneous evaluation of the in vitro release and permeation of oral solid pharmaceutical dosage forms. The release rate in both dissolution devices (USP and F-C-SL apparatus) was evaluated with acetaminophen tablets. Different test conditions (stirring rate and solvent volume ratio) were investigated and no significant differences in acetaminophen release rate were found between these apparatuses. In the F-C-SL apparatus, the in vitro permeation kinetics of acetaminophen were evaluated using synthetic membranes and followed a zero-order kinetic.     

Evaluation of Dosage Forms. VI. Studies of Commercial Oxyphenbutazone Tablet Dosage Forms

Dissolution-dialysis studies of commercial tablets of oxyphenbutazone were carried out to establish the applicability of this technique for the in vitro evaluation of oxyphenbutazone dosage form. While disintegration time and dissolution rate studies did not give a true indication of bioavailability, an excellent correlation was obtained between the dialysis rate constant K and the pharmacokinetic parameters AUC and C_max.     

Bioavailability of Cephalexine Dosage Forms

The bioavailability of 3 brands of cephalexine (tablets, capsules and suspension) using a solution as a reference standard was evaluated in 8 healthy volunteers in a crossover design. Single oral doses of each product were administered at intervals of 1 week. Statistical analysis of the cumulative urinary amount of cephalexine excreted after 12 h, indicated no significant differences among them. Moment analysis was used to estimate the mean dissolution and mean absorption time, showing that dissolution is the rate limiting step in tablets and capsules.     

Bioavailability of Cephalexine Dosage Forms

Abstract

The bioavailability of 3 brands of cephalexine (tablets, capsules and suspension) using a solution as a reference standard was evaluated in 8 healthy volunteers in a crossover design. Single oral doses of each product were administered at intervals of 1 week. Statistical analysis of the cumulative urinary amount of cephalexine excreted after 12 h, indicated no significant differences among them. Moment analysis was used to estimate the mean dissolution and mean absorption time, showing that dissolution is the rate limiting step in tablets and capsules.     

Should Magnesium Stearate be Assessed in the Formulation of Solid Dosage Forms by Weight or by Surface Area ?

Three batches of magnesium stearate differing in morphology, particle size, bulk density and specific surface area were compared in the preparation of Pyrazinamide direct compression tablets. When the lubricants were used in the same amount they gave rise to tablets differing in hardness, disintegration and dissolution. When they were used in such amounts to develop equivalent lubricating areas, the final characteristics of the tablets were almost identical. A direct correlation was found between lubricating areas and ejection force.     

Oral Dosage Development of a Human Rhinovirus and Non-Polio Enterovirus Inhibitor

WIN 63843, a Picornavirus replication inhibitor, is physically and chemically stable in the solid state, to light, elevated temperature, and humidity. This 3-ary15-trifluoromethyl disubstituted 1,2,4-oxadiazole compound has very low water solubility but is highly soluble in ethanol and in safflower seed and corn oils. Solubility in the vegetable oils is doubled by the synergistic effect of ethanol at the 16% alcohol concentration. Vegetuble oil solutions of WIN 63843 are thermally stable but react slowly in the presence of light resulting in an amidoxime compound (WIN 65489) formed by opening of the 1,2,4-oxadiazole ring. This reaction does not occur in oil solutions containing small concentrations of ethanol. Of biophannaceutical interest, the addition of ethanol or PEG-400 solutions of WIN 63843 to human gastric fluid resulted in oily droplet formation whereas crystals form upon addition of these solutions to water. Also, the compound is greater than 8,000 times more soluble in human gastric fluid.     

Oral Dosage Development of a Human Rhinovirus and Non-Polio Enterovirus Inhibitor

Abstract

WIN 63843, a Picornavirus replication inhibitor, is physically and chemically stable in the solid state, to light, elevated temperature, and humidity. This 3-ary15-trifluoromethyl disubstituted 1,2,4-oxadiazole compound has very low water solubility but is highly soluble in ethanol and in safflower seed and corn oils. Solubility in the vegetable oils is doubled by the synergistic effect of ethanol at the 16% alcohol concentration. Vegetuble oil solutions of WIN 63843 are thermally stable but react slowly in the presence of light resulting in an amidoxime compound (WIN 65489) formed by opening of the 1,2,4-oxadiazole ring. This reaction does not occur in oil solutions containing small concentrations of ethanol. Of biophannaceutical interest, the addition of ethanol or PEG-400 solutions of WIN 63843 to human gastric fluid resulted in oily droplet formation whereas crystals form upon addition of these solutions to water. Also, the compound is greater than 8,000 times more soluble in human gastric fluid.