Validation of Liquid Chromatographic Method of Assay for Acetaminophen, Butalbital and Caffeine in Solid Dosage Forms

The validation of a liquid chromatographic procedure for the determination of acetaminophen, butalbital and caffeine in solid dosage forms is described. The dosage content of tablets or capsules is diluted and chromatographed on a Radialpak Cyanopropylsilane Cartridge with a mobile phase of water-acetonitrile-1M dibutylamine phosphate (90+9+1, V/V) with detection at 215 nm. The calibration curve is linear with correlation coefficients of 0.999 for each component. Recoveries of spiked excipient blend averaged 99.5% for acetaminophen, 102.5% for butalbital and 101.0% for caffeine. The method met USP requirements for system suitability with proper resolution between two adjacent peaks. The relative standard deviation (RSD) of peak response of each component (obtained by chromatographing six replicates of standard solution) is less than 2.0% and the tailing factor of each component is not greater than 1.5. The method can be used for composite, content uniformity and dissolution assay of acetaminophen, butalbital and caffeine in tablet and capsule formulations.     

High Performance Liquid Chromatographic Method for the Determination of Diphenhydramine in Liquid and Solid Drug Dosage Forms and Its Application to Stability Testing

Abstract

A simple, precise, rugged, stability-indicating method for diphenhydramine in liquid and solid drug preparations based on reversed phase ion-pair HPLC is described. The eluent used with the C8-bonded phase column, was acetonitrile/0.005 M aq. hexanesulfonic acid/acetic acid (70/30/1,v/v). The liquid product was simply dissolved in acetonitrile/water/acetic acid (70/30/1,v/v) and filtered; the solid product was briefly ground, dissolved in the same solvent, and filtered. The precision (rsd) of the method for diphenhydramine in the liquid sample is 0.52%, and 0.50% for the solid sample. The method is linear up to 200 μg/mL. Based on spiking studies, the recoveries are 100.1% for the liquid sample, and 99.2% for the solid sample. The method was applied to the study of the thermal stability of the drug by following the degradation of diphenhydramine in the two products at temperatures in the 42°C to 62°C range for up to 16 weeks. Shelf lives of the products were determined assuming zero and first order kinetics of decomposition, and are at least 163 days for the liquid product, and at least 255 days for the solid product.     

Disintegrants in Solid Dosage Forms

The dynamic approach to tablet disintegration, which is based on the measurement of the force that develops inside the compact upon water entrance, is basically taken up.

The combined measurements of force development and water uptake, simultaneously effected on the same compact, provide a novel parameter that is proposed to quantify and compare the efficiency of disintegrants.

The new parameter, which is based on the “force-equivalent” concept, expresses the capability of a disintegrant of transforming water uptaken into swelling (or disintegrating) force. A few examples, that illustrate the usefulness of this parameter for disintegrant characterization, are given.

In parallel to the quantification of swelling (or disintegrating) efficiency inside compacts, attention is also being paid to the characterization of swelling disintegrants as pure materials.

In particular the case of the so-called limited swelling materials, for which the quantification of intrinsic swelling (particle volume increase in swelling media) is critical, is considered.

The applicability of an instrumental method, which is based on the employment of a Coulter Counter, is discussed alternatively to microscopic methods.

Disintegrant characterization may also be considered in view of new possible exploitations of the swelling properties of polymers in controlling drug release.     

Disintegrants in Solid Dosage Forms

Abstract

The dynamic approach to tablet disintegration, which is based on the measurement of the force that develops inside the compact upon water entrance, is basically taken up.

The combined measurements of force development and water uptake, simultaneously effected on the same compact, provide a novel parameter that is proposed to quantify and compare the efficiency of disintegrants.

The new parameter, which is based on the “force-equivalent” concept, expresses the capability of a disintegrant of transforming water uptaken into swelling (or disintegrating) force. A few examples, that illustrate the usefulness of this parameter for disintegrant characterization, are given.

In parallel to the quantification of swelling (or disintegrating) efficiency inside compacts, attention is also being paid to the characterization of swelling disintegrants as pure materials.

In particular the case of the so-called limited swelling materials, for which the quantification of intrinsic swelling (particle volume increase in swelling media) is critical, is considered.

The applicability of an instrumental method, which is based on the employment of a Coulter Counter, is discussed alternatively to microscopic methods.

Disintegrant characterization may also be considered in view of new possible exploitations of the swelling properties of polymers in controlling drug release.     

A High Performance Liquid Chromatographic Method for the Simultaneous Assay of aspirin, Caffeine, Dihydrocodeine Bitartrate and Promethazine Hydrochloride in a Capsule Formulation

A method for the simultaneous quantitation of aspirin, caffeine, dihydrocodeine bitartrate and promethazine HCl was developed using reversed-phase, solvent-programming high-performance liquid chromatography. Linear gradient elution with acetonitrile in phosphate buffer (from 15:85 to 56:44) allowed all compounds to elute from a C-18 column within 7 min with adequate resolution. This method also allowed the resolution and quantitation of salicylic acid, the principle decomposition product of aspirin. CV% of eight determinations each of aspirin, caffeine, dihydrocodeine bitartrate and promethazine HCl are 0.64, 1.25, 3.37 and 1.72, respectively, and percent recoveries from spiked preparations were 100.25, 100.03, 100.45 and 98.00, respectively. This assay method was shown also to be suitable for dissolution studies with water or acetate buffer as the dissolution medium.     

A High Performance Liquid Chromatographic Method for the Simultaneous Assay of aspirin,Caffeine, Dihydrocodeine Bitartrate and Promethazine Hydrochloride in a Capsule Formulation

Abstract

A method for the simultaneous quantitation of aspirin, caffeine, dihydrocodeine bitartrate and promethazine HCl was developed using reversed-phase, solvent-programming high-performance liquid chromatography. Linear gradient elution with acetonitrile in phosphate buffer (from 15:85 to 56:44) allowed all compounds to elute from a C-18 column within 7 min with adequate resolution. This method also allowed the resolution and quantitation of salicylic acid, the principle decomposition product of aspirin. CV% of eight determinations each of aspirin, caffeine, dihydrocodeine bitartrate and promethazine HCl are 0.64, 1.25, 3.37 and 1.72, respectively, and percent recoveries from spiked preparations were 100.25, 100.03, 100.45 and 98.00, respectively. This assay method was shown also to be suitable for dissolution studies with water or acetate buffer as the dissolution medium.     

High Pressure Liquid Chromatographic Assay for Haloperidol

A high pressure liquid chromatographic assay for haloperidol in aqueous solutions is presented. This assay permits the separation and quantitation of drug concentrations below 100 ng/ml.     

Preformulation Studies of Drug Substances for Solid Dosage Forms

Abstract

Azelastine hydrochloride, an investigational drug, was observed to form a hydrate or solvates upon recrystallization. X-ray diffraction and thermal analytical studies indicate that the hydrate or solvates exist in crystalline forms different from that of the parent material. Thermal analytical techniques confirmed that azelastine forms hydrate or solvates as opposed to a polymorph. The enthalpies and entropies of transitions were determined. A difference in dissolution rate of unrecrystallized and recrystallized azelastine was found.     

High Performance Liquid Chromatographic Assay for Papaverine in Plasma

A simple and sensitive assay for papaverine in plasma was developed. Plasma was extracted into n-heptane and back extracted into 0.1 N HCl. An aliquot of 0.1 N HC1 was injected onto a reversed-phase column. The mobile phase consisted of 33% acetonitrile in 0.05 M phosphate buffer, pH 3.0, at a flow rate of 1.6 ml/min. The retention times of papaverine and the internal standard (diphenylhy-dramine hydrochloride) were 4.0 and 7.0 minutes respectively. The coefficient of variation over 2-50 nanogram/ml range for spiked samples (n = 6) was 9.9% suitability of this method for plasma sample analysis from a bioavailability study was demonstrated.     

Preformulation the Role of Moisture in Solid Dosage Forms

Moisture plays an important role in the individual stages of preformulation studies for solid dosage forms. Examples are given to demonstrate this

The first stage involves chemical tests with the pure active substance using a reliable storage scheme. Then compatibility testing between active and inactive substances is performed. Under the general heading of sorption tests, the determination of sorption isotherms using special apparatus and their correlation with the physical and chemical changes which occur in the samples are discussed. With the results of these tests it is often possible to influence the sorption properties of the finished dosage form, for example by selection of the excipients and the salt form of the active substance, or by deferring the point of ansorption

Finally, as an example of special tests used in pre-formulation, the development of compound preparations is described and the galenical pre-stages are discussed     

Preformulation the Role of Moisture in Solid Dosage Forms

Abstract

Moisture plays an important role in the individual stages of preformulation studies for solid dosage forms. Examples are given to demonstrate this

The first stage involves chemical tests with the pure active substance using a reliable storage scheme. Then compatibility testing between active and inactive substances is performed. Under the general heading of sorption tests, the determination of sorption isotherms using special apparatus and their correlation with the physical and chemical changes which occur in the samples are discussed. With the results of these tests it is often possible to influence the sorption properties of the finished dosage form, for example by selection of the excipients and the salt form of the active substance, or by deferring the point of ansorption

Finally, as an example of special tests used in pre-formulation, the development of compound preparations is described and the galenical pre-stages are discussed     

Aging Effect on Stability and Eioavailability of Glibenclamide in Solid Dosage,Forms

Abstract

Asing effect of some solid dosage form of glibenclamide, after storage at various storage conditions and accelerated temperatures for certain length of time, affected percentage degradation, physical. properties, in-vitro dissclution and in- vivo performances, has been, investigated and compared with the marketed tablets of Dionil®. The percentage degradation responding to accelerated conditions has been extrapolated by formal Arrhenius treatment. Fowever, maximum stability and highest shelf-life of direct compression, lactose tablets, followed by Dionll^R and then suppositories have been observed. The aging and elevation of temperature, adversely affected dissolution rate and indicated a decrease In bioavailability of glibenclamide based on C_max, and T_max and AUC.     

Aging Effect on Stability and Eioavailability of Glibenclamide in Solid Dosage, Forms

Asing effect of some solid dosage form of glibenclamide, after storage at various storage conditions and accelerated temperatures for certain length of time, affected percentage degradation, physical. properties, in-vitro dissclution and in- vivo performances, has been, investigated and compared with the marketed tablets of Dionil®. The percentage degradation responding to accelerated conditions has been extrapolated by formal Arrhenius treatment. Fowever, maximum stability and highest shelf-life of direct compression, lactose tablets, followed by Dionll^R and then suppositories have been observed. The aging and elevation of temperature, adversely affected dissolution rate and indicated a decrease In bioavailability of glibenclamide based on C_max, and T_max and AUC.     

Development and Validation of a High-Performance Liquid Chromatographic Method for the Analysis of Propylthiouracil in Pharmaceuticals

A simple, rapid, and stability-indicating high-performance liquid chromatographic (HPLC) method was developed and validated for the assay of propylthiouracil (PTU). The method was used to quantify PTU in topical formulations and in tablets. Excellent linearity was observed between PTU concentration and the peak area (R² = 0.999). The limit of detection was 1 ng, and the limit of quantitation was 1.2 ng. The method proved to be selective. Selectivity was validated by subjecting a stock solution of PTU to acidic, basic, and oxidative degradations. The peaks of the degradation products did not interfere with the peak of PTU. Excipients present in the dosage forms did not interfere with the analysis, and the recovery of PTU from each dosage form was quantitative.     

Development and Validation of a High-Performance Liquid Chromatographic Method for the Analysis of Propylthiouracil in Pharmaceuticals

A simple, rapid, and stability-indicating high-performance liquid chromatographic (HPLC) method was developed and validated for the assay of propylthiouracil (PTU). The method was used to quantify PTU in topical formulations and in tablets. Excellent linearity was observed between PTU concentration and the peak area (R² = 0.999). The limit of detection was 1 ng, and the limit of quantitation was 1.2 ng. The method proved to be selective. Selectivity was validated by subjecting a stock solution of PTU to acidic, basic, and oxidative degradations. The peaks of the degradation products did not interfere with the peak of PTU. Excipients present in the dosage forms did not interfere with the analysis, and the recovery of PTU from each dosage form was quantitative.     

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

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 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.