Noelia L. Gonzalez Vidal

Dissolution Stability Study of Cefadroxil Extemporaneous Suspensions

Dissolution studies have become matter of great significance because, in most cases, drug dissolution is the rate-limiting step in the absorption process. As occurs with solid oral dosage forms, heterogeneous disperse systems (suspensions) could also have some problems with their in vitro dissolution. The dissolution behavior of four different brands of cefadroxil extemporaneous suspensions available in the Argentinian market was evaluated. The deliverable volume, pH, visual appearance, uniformity of dosage units, and assay were also studied. Powders for oral suspension were stored under different aging conditions. Samples at room temperature and refrigerated conditions were taken at several time points to carry out the dissolution stability study during the expiration period of the reconstituted form. Marked differences were recorded with respect to in vitro dissolution behavior between the different products under evaluation.

Albendazole Solid Dispersions: Influence of Dissolution Medium Composition on In Vitro Drug Release

Fil: Gonzalez Vidal, Noelia Lujan. Consejo Nacional de Investigaciones Cientificas y Tecnicas; Argentina. Universidad Nacional del Sur. Departamento de Biologia, Bioquimica y Farmacia. Catedra de Control de Calidad de Medicamentos; Argentina

Comparative dissolution studies of albendazole oral suspensions for veterinary use

Fil: Gonzalez Vidal, Noelia Lujan. Universidad Nacional del Sur. Departamento de Biologia, Bioquimica y Farmacia. Catedra de Control de Calidad de Medicamentos; Argentina. Consejo Nacional de Investigaciones Cientificas y Tecnicas; Argentina

UV Analytical Method Suitability for Investigation of BCS Class 2 Biowaivers: Ibuprofen Case

Biowaivers are scientifically justified for immediate-release oral dosage forms containing BCS Class 2 drugs. Therefore, a comparison of in vitro dissolution profiles via similarity factor calculation is expected. If a difference greater than 10% cannot be detected by the analytical method, then the f2 similarity factor will not detect any differences between profiles. The aim of the present study was to evaluate the sensitivity of UV measurements of a Class 2 drug, ibuprofen, at the three physiological pH values of biowaiver analysis and at the different wavelengths according to USP and Ph. Eur. The slope of the calibration curve and the discriminant capacity were calculated to evaluate the sensitivity of each method. It was concluded that at 264/272 nm (identification Ph. Eur. and USP wavelengths), the analytical method is not suitable for ibuprofen biowaiver investigation, while at 220/221 nm (USP dissolution test), the UV method has adequate sensitivity. INTRODUCTION The Biopharmaceutics Classification System (BCS) guidances (1, 2) allow a waiver of in vivo bioequivalence studies for immediate-release oral dosage forms containing BCS Class 1 drugs (rapidly dissolving and with similar dissolution profiles to the reference product at pH values of 1.2, 4.5, and 6.8). Further discussions and subsequent publications (3, 4) recommend that biowaivers can be extended to BCS Class 2 weak acids (high solubility at pH 6.8 but not at pH 1.2 or 4.5, high permeability) if the multisource product is rapidly dissolving at pH 6.8 and its dissolution profile is similar to that of the reference at the three pH values. Ibuprofen (IBU) is a Class 2 drug (5); therefore, biowaivers for its immediate-release dosage forms are under investigation (6, 7). Besides, this NSAID is one of the most-used anti-inflammatory drugs, with a large number of different formulations available. Dissolution profile similarity may be determined using the f2 factor. When two profiles are identical, f2 has a value of 100. An average difference of no more than 10% at any sample time point of the profiles may be acceptable, and this represents a similarity factor of 50. The dissolution profile of a test batch is therefore considered similar to that of the reference product if the f2 value is not less than 50 (8). The ability of the in vitro dissolution test to detect differences is of great importance for biowaiver definitions. Thus, the sensitivity of the analytical method used to measure the dissolution samples is also of great importance. The USP dissolution test for IBU immediaterelease tablets uses quantification by UV spectrophotometry at the wavelength of maximum absorbance (about 221nm), while HPLC with UV detection at 220 nm is recommended for IBU oral suspensions (9). According to USP (9) and Ph. Eur. (10), IBU is identified by UV absorption at about 264 and 272/273 nm in 0.1 N sodium hydroxide. It is known that absorbance wavelength and sensitivity of measurements can vary according to the solvent in which the analyte is dissolved. Investigation of the possibility of biowaivers for IBU was carried out by Alvarez et al. (7) using UV spectrophotometry according to Ph. Eur. The purpose of the present study was to evaluate the sensitivity of UV measurements of a Class 2 drug, IBU, at the three physiological pH values and different wavelengths according to USP and Ph. Eur., to verify the suitability of the analytical method for biowaiver studies. The sensitivity of each method was evaluated through the slope of the calibration curve and the discriminant capacity. MATERIALS AND METHODS Reagents IBU Ph. Eur. bulk drug (99.8% purity, 0.100% humidity) was purchased from Guinama (Valencia, Spain). Hydrochloric acid, glacial acetic acid, potassium chloride, sodium acetate trihydrate, sodium hydroxide, and monobasic potassium phosphate were purchased from Panreac (Barcelona, Spain). High purity deionized water was obtained from a Milli-Q purification system (Millipore, Bedford, USA). Buffer solutions of pH 1.2, 4.5, and 6.8 were prepared according to USP (9). Equipment The pH values of buffer solutions were measured with a Crison pH meter (model GLP 22). A UV–vis doublebeam spectrophotometer (Shimadzu UV–1700 PharmaSpec) was used. *Corresponding author. e-mail: nlgvidal@uns.edu.ar dx.doi.org/10.14227/DT200113P44

Dissolution Stability of Cephalexin Extemporaneous Suspensions During an Accelerated Stability Study

The aim of the present study was to evaluate the influence of accelerated aging conditions on drug content and in vitro dissolution stability of three cephalexin (CE) extemporaneous suspensions obtained from pharmacies and a local state laboratory. The specific gravity, pH, and visual appearance of CE oral extemporaneous suspension were also studied. Dissolution profiles were performed according to FDA recommendations, since there is no official dissolution method codified. Analyses were performed throughout the administration period of the reconstituted suspension (7 days at room temperature storage or 14 days under refrigeration), at time zero, and during twelve months of storage of the powders under ICH accelerated aging conditions. Dissolution Efficiency (DE) values and assay results were analyzed via analysis of variance (ANOVA) to evaluate the effect of aging conditions on the stability of each formulation. From a clinical point of view, the storage conditions applied did not affect dissolution or chemical stability of CE oral extemporaneous suspensions. INTRODUCTION Cephalexin (CE) oral suspensions are useful and effective pharmaceutical formulations for patients hypersensitive to penicillin and for patients who have difficulty swallowing solid dosage forms. Cephalosporins are active pharmaceutical ingredients used worldwide in oral formulations because of their proven track record of broad-spectrum antibacterial activity and excellent safety over more than thirty years of clinical use (1, 2). CE is a first-generation cephalosporin antibiotic used to treat infections of the urinary tract, respiratory tract, skin, and soft tissue (3). CE is almost completely absorbed from the gastrointestinal tract and produces a peak plasma concentration one hour after a 500-mg oral dose. Absorption may be delayed if taken with food. CE is widely distributed in the body, and its half-life is about one hour. It is not metabolized, and about 80% or more of a dose is excreted unchanged in the urine (4). Physical stability of extemporaneous suspensions is a parameter not often considered but of crucial evaluation due to the consequences it can have on drug bioavailability. Stability studies carried out on extemporaneous products only monitor changes in chemical stability, visual appearance, pH, caking, and redispersability, with no focus on in vitro dissolution stability (5–7). Suspensions can be considered analogous to the disintegrated forms of tablets and capsules. If in vitro dissolution evaluation is a priority for the latter, it is logical to extend the requirement to suspensions as a limiting step to absorption and bioavailability (6–8). However, fewer than 10% of codified oral suspensions have a dissolution test described (9, 10), and to the best of our knowledge, among the few studies carried out on suspension dissolution, almost none of them consider changes in dissolution during the administration period of the reconstituted form (11–18). If a product is stored under the conditions specified on the label, it is expected to maintain its initial dissolution behavior throughout its life, which is known as Dissolution Stability (19). This concept is a critical biopharmaceutical parameter because of the potential impact it may have on the bioavailability of the product. Therefore, it is essential that the dissolution characteristics of a pharmaceutical formulation, whether tablet, capsule, or even suspension (5), remain unchanged throughout its shelf life. In a previous work (20), the appropriate general conditions for performing dissolution profiles of extemporaneous suspensions were established. Our research attempted to evaluate if ICH accelerated storage conditions (21) also significantly affect the dissolution stability of another cephalosporin antibiotic, such as CE. The aim of the present work was to evaluate and compare the influence of these aging conditions on the drug content and in vitro dissolution stability of three different CE suspensions in the Argentinean market during the administration period and during twelve months of powder storage. MATERIALS AND METHODS Reagents and Samples Analytical grade potassium dihydrogen phosphate and HPLC grade methanol, acetonitrile, and water (J. T. Baker, USA) were used for chromatographic determinations. Distilled water was used as dissolution medium. CE monohydrate reference standard was purchased from INAME (ANMAT, Argentina). Two CE extemporaneous oral suspensions, manufactured by different pharmaceutical compa*Corresponding author. e-mail: concal@uns.edu.ar dx.doi.org/10.14227/DT190312P23

A Comparative In Vitro Assay of Drug Release Performance of Pyridostigmine Bromide Tablets

Myasthenia gravis is an autoimmune disease that destroys key components of the neuromuscular system. The most common therapy uses reversible inhibitors of cholinesterase activity, such as pyridostigmine bromide (PB). The nature of this illness implies that we must be sure that all available PB immediate-release tablets produce the same therapeutic response. The aim of this study was to analyze PB immediate-release formulations provided by pharmacies in MERCOSUR countries A, B, and C. The formulations, which were produced in different manufacturing plants of the same multinational company, were analyzed following USP 29 specifications. The products fulfilled the assay, uniformity of dosage units, and dissolution test in S2 stage. Dissolution profiles were carried out following EMEA and FDA regulations, and the similarity factor (f2) was applied to A and C but not B, as this one did not fulfill the dissolution requirements. Pyridostigmine bromide tablets from countries A and C are considered to be similar and could be interchangeable. Formulation B exhibited such different dissolution behavior that its interchangeability is discouraged, as well as its introduction in countries A and C from the manufacturing country B.