In Vitro Dissolution Kinetics of Amlodipine Tablets Marketed in Russia Under Biowaiver Conditions

The current paper is devoted to in vitro dissolution kinetics studies of amlodipine tablets marketed in Russia under biowaiver conditions. Dissolution kinetics studies were carried out according to WHO Guidance. Dissolution profiles of test and reference (innovator) amlodipine tablets were considered equivalent. INTRODUCTION Over the past three decades, dissolution testing has evolved into a powerful tool for characterizing the quality of oral pharmaceutical products. For some solid dosage forms containing active pharmaceutical ingredients with special properties, a comparative in vitro dissolution profile similarity can be used to establish equivalence of test with reference product. Such studies, used to approve equivalence other than through in vivo equivalence testing, are called “biowaiver” (1). Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. It is indicated for the treatment of hypertension, chronic stable angina, and confirmed or suspected vasospastic angina (2). The chemical name of amlodipine is 3-ethyl 5-methyl 2-[(2aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4dihydropyridine-3,5-dicarboxylate. Its structure is shown in Figure 1. Solubility Amlodipine is described as slightly soluble in water in different Pharmacopoeias (3, 4). The experimental water solubility for amlodipine is 75.3 mg/L (5). The lowest solubility in the pH range from 1 to 6.8 at 37 °C is 1 mg/mL (1). Within the gastrointestinal pH range, amlodipine is an ionized compound (weak base) (5). The pKa of amlodipine is about 8.6 at 25 °C (5). Dosage form strength is expressed in mg of salt and is not equivalent to the free base. Amlodipine is listed in the WHO Model list of medicines as an antihypertensive medicine in a 5-mg tablet strength (6). Russia has Marketing Authorizations for amlodipine as an immediate-release dosage form in strengths of 2.5; 5, and 10 mg (7). Thus the D/S ratio for the amlodipine WHO Model List of Essential Medicines dose (5 mg) at a pH range of 1.2–6.8 is 5 mL and 10 mL for the highest dose marketed in Russia. Therefore, amlodipine is a “highly soluble” drug according to WHO Guidance (D/S ratio ≤ 250 mL). Permeability When an active pharmaceutical ingredient is absorbed to an extent of 85% or more, it is considered “highly permeable. ” Amlodipine’s absolute bioavailability is 60–65%, but its permeability is classified as “high” due to metabolite excretion in urine (90–95%). Taking amlodipine solubility and permeability into account, according to WHO Guidances, amlodipine is assigned to BCS Class I (1). Thus, amlodipine in vitro equivalence may be evaluated under biowaiver conditions for BCS Class I (1). MATERIALS AND METHODS Chemicals Analytical grade concentrated hydrochloric acid, glacial acetic acid, potassium dihydrophosphate, disodium hydrophosphate dodecahydrate, and potassium chloride were used. e-mail: ramenskaia@mail.ru *Corresponding author. Figure 1. Structure of amlodipine. diss-17-03-04.indd 20 8/18/2010 1:42:43 PM dx.doi. org/10.14227/DT170310P20