Classification of torasemide based on the Biopharmaceutics Classification System and evaluation of the FDA biowaiver provision for generic products of Class I drugs

Abstract

The biopharmaceutical properties of an in-house developed new crystal modification of torasemide (Torasemide N) were investigated in comparison with the most well known crystal modification form of torasemide (Torasemide I) in order to classify the drug according to the Biopharmaceutics Classification System (BCS), and to evaluate the data in line with current US Food and Drug Administration (FDA) guidance (with biowaiver provision for Class I drugs) to determine if the biowaiver provision could be improved. The solubility profiles of Torasemide I and Torasemide N were determined, and tablets prepared from both forms of the drug were studied for in-vitro release characteristics in media recommended by the current FDA guidance for biowaiver of generic products, and in other media considered more appropriate for the purpose than the ones recommended by the FDA. Two separate bioequivalence studies in healthy humans (following oral administration) were performed with two test products (both prepared from Torasemide I) against a single reference product (prepared from Torasemide N). The absorption profiles of the drug from the tablets were determined by deconvolution for comparison with the in-vitro release profiles to determine the appropriateness of some dissolution media for predicting in-vivo performance and to determine the comparative rate and extent of absorption. The drug was absorbed from the tested products quickly and almost completely (about 95% within 3.5 h of administration). However, one test product failed to meet the bioequivalence criteria and had a significant initial lower absorption rate profile compared with the reference product (P< or =0.05), whereas the other product was bioequivalent and had a similar absorption profile to the reference product. A dissolution medium at pH 5.0, in which torasemide has minimum solubility, was found to be more discriminatory than the media recommended by the FDA. Torasemide has been classified as a Class I drug according to the BCS up to a maximum dose of 40 mg and the data suggest that the current FDA guidance could be improved by giving more emphasis to selection of appropriate dissolution media than is given in its current form for approving biowaiver to generic products of Class I drugs.

Evolution of Choice of Solubility and Dissolution Media After Two Decades of Biopharmaceutical Classification System

“…Also, the phosphate buffer failed to adequately discriminate and distinguish between products of torasemide, a class I drug according to the BCS, in a biowaiver approach. In this case, a medium at pH 5.0 discriminated better among these products and was superior to the FDA-recommended medium (75).…”

“…As mentioned, biorelevant media contain generally components which are likely present in the human GI tract such as bile salts and lecithin aiming to mimic the physiological conditions in specific segments of the GI tract; thus, in these media, pH, osmolality, and surface tension are adapted to physiological values (75).…”

Crystalline salts of a diuretic drug torasemide with improved solubility and dissolution properties

“…14,15,23,24 The torasemide drug suffers from poor aqueous solubility and wettability issues 16,25,26 and its solubility profiles are pH dependent due to its amphoteric nature. 27 A few strategies have been attempted to increase the solubility of the torasemide drug by crystal/solid form modification (polymorphs, solvates, salts, amorphous state), 16,[25][26][27][28][29][30][31][32] solid dispersions and the use of super disintegrating additives 33,34 for faster dissolving tablet formulations, etc. The crystal form modification approach has resulted in moderate solubility improvements (2-3 times).…”

“…The crystal form modification approach has resulted in moderate solubility improvements (2-3 times). 16,[25][26][27][28][29][30][31][32] Gutman et al in a US patent 20 discloses a crystalline hydrochloride salt of torasemide; however, dissolution and solubility studies of torasemide salts are lacking. We therefore chose to screen this drug for salt formation with some of the acceptable safe coformer molecules from the list of the Food and Drug Administration's generally recognized as safe (FDA-GRAS) chemicals and pharmaceutical excipients.…”

Novel biopharmaceutical development investigations towards drug and formulation performance optimization

“…As mentioned before, biorelevant media were made to simulate the GI tract pH and components likely to be found in the human GI tract, such as bile salts and lecithin. Osmolality, pH and surface tension are adapted to physiological values (207). Food can have an impact on a drug's in vivo dissolution and further absorption.…”