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    Biowaiver monograph for ascorbic acid immediate release solid oral dosage forms
    (2016) Helen Najdi Naji Al-Masri; Dr. Ramzi Shawahna; Dr. Amjad Hussien
    Background: Demonstrating similarity in terms of safety and efficacy between innovator pharmaceutical products and their generic versions is a critical step in granting marketing authorizations (MAs) for generics. Similarity often proved by conducting in vivo bioequivalence (BE) studies in healthy volunteers. Health regulatory bodies issue MAs for generic versions after furnishing a proof of similarity with their innovator counterparts. BE studies are expensive, time consuming and risky studies since they are conducted in healthy volunteers. Today, the biopharmaceutical classification system (BCS) introduced by Amidon and adapted by various regulatory authorities and organizations like the US Food and Drug Administration (FDA), European Medicines Agency (EMA) and the World Health Organization (WHO) has significantly changed the processes of drug development and approval. Regulatory bodies now allow waiver of in vivo BE studies using surrogate in vitro dissolution testing for immediate release (IR) solid oral dosage forms containing high solubility and high permeability (BCS class I) drugs. Objectives: The objectives of this thesis were to systematically evaluate the possibility of granting biowaiver for immediate release (IR) formulations containing ascorbic acid as an active pharmaceutical ingredient (API). The release characteristics of two formulations containing ascorbic acid were also assessed. Methods:Solubility studies were conducted to determine the aqueous solubility of ascorbic acid at different pH points in the range of 1-7.5 at 37 ºC and to assign a correct solubility class for ascorbic acid. According to the BCS, and the FDA guidelines, a drug substance is considered highly soluble when the highest dosestrength is soluble in 250 ml or less of aqueous media over the pH range of 1–7.5. A standard shake-flask method was applied using three different aqueous media with pH values of 1.0 (maleate buffer), 4.5 (acetate buffer), and 7.5 (phosphate buffer) at 37 °C. The establishment of equilibrium was confirmed by comparing the solubility at 24 h and 48h.Drug levels in the samples were analyzed using UV spectrophotometric assay of ascorbic acid at 260nm. Dissolution experiments on two IR tablets containing ascorbic acid 500 mg were carried out. Dissolution profiles of ascorbic acid 500 mg tablets were generated in 900 ml of deionized water at pH points of 1.2, 4.5 and 6.8 adjusted using 0.1 N HCl or NaOH solutions. A paddle type dissolution apparatus was used and dissolution was tested in according to the USP type-II method. Paddles rotated at 75 rpm and the temperature of the dissolution media was maintained at 37 ± 0.5 ºC. Aliquots of 5 mL were withdrawn at predetermined time intervals of 5, 10, 15, 20, 25, 30, 45 and60 min.Samples were suitably diluted and analyzed at260 nm using UV spectrophotometer. Molecular descriptors like polar surface area (PSA), n-octanol/water partition coefficient (log P), distribution-coefficient at pH 7.4 (log D7.4), number of hydrogen bond acceptors, number of hydrogen bond donors and pKa were calculated using software packages. Literature databases were searched for solubility, permeability and dissolution related parameters. Results:The solubility measurements show that the maximum dose listed on the WHO’s EML list was soluble in less than 250 mL of water over the pH range specified by the regulatory agencies at 37 °C. The calculated dose number was in the range 0.00011 of 0.00029 in the pH range of 1.2-7.5. These results suggest that ascorbic acid should unequivocally be assigned a “high solubility” BCS class. Based on the predicted physicochemical properties and observed in vivo behavior, ascorbic acid behave like high permeability BCS class drugs. Therefore, we suggest that ascorbic acid should be assigned to BCS class I drugs. Visual as well as similarity (ƒ2) and difference (ƒ1) factors comparisons between the two IR oral formulations containing ascorbic acid(C-Tamin tablets, and Vitamin C tablets) as a single API showed the ascorbic acid was released differently in the tested dissolution media. Conclusions:Ascorbic acid is a high solubility and high permeability drug, and therefore is classified as a BCS class 1 compound. The risk of bioinequivalence is manageable as long as the use of ascorbic acid is safe. For these reasons, we consider ascorbic acid to be a good candidate for waiver of in vivo BE studies. Conducting in vitro dissolution could reveal the quality of IR oral formulations. Key words:absorption; bioavailability; bioequivalence; biopharmaceutical classification system (BCS); biowaiver; ascorbic acid; pharmacokinetics; permeability; solubility