Investigation of Biowaivers for Immediate Release Formulations Containing BCS III Drugs, Acyclovir, Atenolol, and Ciprofloxacin Hydrochloride, Using Dissolution Testing

Abstract

The dissolution of several products containing Biopharmaceutical Classification System (BCS) class III drugs, acyclovir, atenolol, and ciprofloxacin hydrochloride, listed in the WHO essential drug list (EDL), was tested and compared with their respective comparator pharmaceutical products (CPPs) marketed in South Africa and India. US Pharmacopeia (USP) buffers of pH 1.2, 4.5, and 6.8 were used as dissolution media and tested using USP apparatus 2 at 75 rpm and 900 ml. Nine acyclovir products were tested, and only three dissolved very rapidly in all media; i.e., they showed a release of >85% in 15 min. Eight atenolol products tested were all very rapidly dissolving in all three pH media. Ten ciprofloxacin hydrochloride products were tested, and the results showed that only five products met the WHO biowaiver criteria. This study indicates that not all marketed products containing the same BCS III active pharmaceutical ingredient (API) in similar strength and dosage form are necessarily in vitro equivalent as per the WHO biowaiver criteria. Furthermore, selection and availability of an innovator product as CPP are important considerations that can affect the outcomes of such studies.

Biowaiver Study of Immediate Release Glimepiride Tablets

“…OB and D2, which had different strength values ( fig. 3), had more than 85% of the drug released within 15 min, which revealed the finding that not only content of drugs and the manufacturing conditions, affect drug release but also formula factors, such as disintegrates and diluents types play an important part in the disintegration of tablet and dissolution profiles.Based on biowaiver study results, D1 sample in pH 7.8 is not bioequivalent with the OB unless further an in vivo bioequivalent studies prove that as it comparable to Reddy, N. H., et al, finding that some but not all Acyclovir, Atenolol, and Ciprofloxacin Hydrochloride products met the biowaiver criteria [35]. Excipients and additives used in manufacturing tablets have great effects on their dissolution, therefore to achieve biowaiver according to regulatory rules, good manufacturing practice should be followed and careful selection of the excipients used is mandatory.…”

Therapeutic Equivalence Evaluated Through In Vitro Studies of Multi-Source Drugs: A Moxifloxacin Case Study in Lima, Peru

“…Another study carried out in the United Arab Emirates in 2017 evaluated five multi-source products of amoxicillin/clavulanic acid tablets (875 mg/125 mg), finding that only three products were bioequivalent with the innovator based on dissolution profiles (i.e., releasing more than 85% of the amount declared in the first 15 minutes) (25). A study carried out in 2017 showed that of 10 multi-source products of ciprofloxacin (500 mg tablets; four from South Africa and six from India), only five (two from South Africa and three from India) were bioequivalent with the reference product because they met the bio-exemption criteria proposed by the WHO (26). Similar results were obtained by a study carried out in India in 2017, which evaluated dissolution and bioequivalence profiles in healthy volunteers, finding that a multi-source product of amoxicillin capsules (500 mg) was not bioequivalent with the reference product (27).…”

Simulation-based comparison of Biopharmaceutics Classification System and drug structure

“…The FDA definition of high solubility is that the highest dose allowed for a single drug administration can be dissolved in 250 ml or less of an aqueous solution at 37℃ and pH1.0-7.5. The other regulatory bodies narrow the pH range to 1.2-6.8 or 1.0-6.8 [23]. In this study, we followed the classification from the World Health Organization.…”