Toward Global Standards for Comparator Pharmaceutical Products: Case Studies of Amoxicillin, Metronidazole, and Zidovudine in the Americas

Löbenberg, Raimar; Chacra, Nádia Araci Bou; Stippler, Erika; Shah, Vinod P.; DeStefano, Anthony J.; Williams, Roger L.

doi:10.1208/s12248-012-9350-9

Cited by 32 publications

(48 citation statements)

References 10 publications

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“…However, two products that carry the same name can be assumed to be identical. This is similar to results reported by Löbenberg et al (20) for metronidazole products with an identical name. It is also imperative for generic preparations to show similarity to the innovator with respect to safety, efficacy, and quality.…”

Section: Discussionsupporting

confidence: 92%

Comparing the Dissolution Profiles of Seven Metformin Formulations in Simulated Intestinal Fluid

Stuart¹,

Clement²,

Sealy³

et al. 2015

Dissolution Technol.

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Dissolution testing is used to evaluate the performance of pharmaceutical products. This study compared the dissolution profiles of seven immediate-release metformin 500-mg formulations, including two products with the trade name Glucophage, in simulated intestinal fluid (SIF) at pH 6.8 buffer without enzymes. Other characteristics investigated were absolute weight and drug content. These formulations were marketed in Trinidad and Tobago and are categorized as Class 3 drugs by the Biopharmaceutics Classification System (BCS). The paddle apparatus was used at 75 rpm in 900 mL of SIF at 37 ± 0.5 °C. Samples of 1.25 mL were removed at 10, 15, 20, 30, 45, and 60 min without replacement, of which 100 µL was diluted with fresh medium and then analyzed spectrophotometrically at 233 nm. Data were analyzed statistically using one-way analysis of variance and DDSolver Add-In to Excel. The weights were significantly different (p ≤ 0.05), and each of the formulations demonstrated drug content between 99% and 103%. Only one of the formulations showed <85% drug release in 15 min and a calculated f 2 value less than 50, which deviates from the acceptance criteria recommended by the World Health Organization (WHO).

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Section: Discussionsupporting

confidence: 92%

Comparing the Dissolution Profiles of Seven Metformin Formulations in Simulated Intestinal Fluid

Stuart¹,

Clement²,

Sealy³

et al. 2015

Dissolution Technol.

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“…Different zidovudine formulations compared to that in our study, were examined in the research done by Löbenberg et al and all products were demonstrated to be similar to the innovator product identified, which was Retrovir® 300-mg capsules, from USA; including another capsule product labeled Retrovir®, from Mexico [22].…”

Section: Zidovudinementioning

confidence: 77%

“…Nevertheless, at pH 4.5 and 6.8, which is considered the range of lowest solubility (pH 4 to 6), the hydrated amoxicillin dissolved slower and drug dissolution increased with time [20]. A study by Löbenberg et al investigated amoxicillin in the Americas and concluded that all products fulfill the requirements in the SGF showing a decline after obtaining a peak at about 10 to 15 min [22]. Nevertheless, some of the products in Löbenberg's study showed similar results to our study and did not release 85% or more of amoxicillin in 15 to 30 min or failed f 2 comparison in buffers 4.5 and SIF.…”

Section: Discussion Amoxicillinmentioning

confidence: 99%

“…Hence, knowledge of whether the dose proportionality concept or another manufacturing procedure was utilized for the 400-and 200-mg metronidazole formulations can assist in understanding the behavior of these products [39]. Löbenberg et al also looked at some metronidazole formulations and reported that the generics examined were not comparable to the innovator product, Flagyl® [22]. Furthermore, there were two products labeled with the trade name Flagyl®; one from Pharmacia, a subsidiary of Pfizer, which was used as the comparative pharmaceutical product according to the Orange Book [16], and the other from Sanofi Aventis.…”

Section: Metronidazolementioning

confidence: 99%

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Investigating the Dissolution Profiles of Amoxicillin, Metronidazole, and Zidovudine Formulations used in Trinidad and Tobago, West Indies

2014

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Abstract. Trinidad and Tobago is a twin-island Republic in the Caribbean and like many developing countries, it has included generic drugs on the national drug formulary to decrease the financial burden of pharmaceutical medications. However, to ensure that medications received by patients are beneficial, generic drugs need to be interchangeable with the innovator which has demonstrated safety, efficacy, and quality. The objective of the study was to compare the dissolution profiles and weight variations for different formulations of amoxicillin, metronidazole, and zidovudine that are on the national drug formulary and marketed in Trinidad and Tobago. All the products investigated are categorized as class 1 drugs according to the Biopharmaceutics Classification System (BCS) and the dissolution profiles were assessed according to the World Health Organization (WHO) criteria for interchangeability between products. The similarity factor, f 2 , was used to determine sameness between the products. No generic formulation was found to be similar to Amoxil® 500-mg capsules. The two generic products for metronidazole 200-mg tablets demonstrated more than 85% drug release within 15 min in all three of the buffers; however, their 400-mg counterparts did not fulfill this requirement. The zidovudine 300-mg tablet complied with the requirements in buffer pH 4.5 and simulated gastric fluid (SGF) but not for simulated intestinal fluid (SIF). Some Class 1 pharmaceutical formulations may possess the same active ingredient and amount of drug but may show significant differences to in vitro equivalence requirements. Nevertheless, the dissolution process is suitable to detect these variations.

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“…Today, amoxicillin is a BCS class I drug substance according to the WHO list of essential drugs (135,136). EMA classifies it as BCS class II drug substance due to the highest dose criterion and FDA as BCS class IV drug substance due to differences in the permeability criterion.…”

Section: Regulatory View Of Biopharmaceutics Drug Classification Systmentioning

confidence: 99%

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

Bou‐Chacra

Melo

Morales

et al. 2017

AAPS J

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Abstract.The introduction of the biopharmaceutics drug classification system (Biopharmaceutics Classification System (BCS)), in 1995, provided a simple way to describe the biopharmaceutics behavior of a drug. Solubility and permeability are among the major parameters, which determine the fraction dose absorbed of a drug substance and consequently its chances to be bioavailable. The purpose of this review is to summarize the evolution of the media used for determining solubility and dissolution and how this can be used in modern drug development. Over the years, physiologically adapted media and buffers were introduced with the intention to better predict the in vivo solubility and dissolution of drug substances. Water, buffer solutions, compendial media, micellar solubilization media, and biorelevant media are reviewed. At this time point, there is no universal medium available which can be used to predict every drug substance's solubility or a drug product's in vivo dissolution behavior. However, there have been many improvements and additions made to media to optimize their in vivo predictability; for example, the current phosphate concentrations in buffers seem to be too high to correlate with the carbonate buffer concentrations in vivo. Biorelevant media were updated to correlate them better with the composition of human intestinal fluids. The BCS was introduced into regulatory sciences as a scientific risk management tool to waive bioequivalence studies under certain conditions. Today's different guidance documents define the dose-solubility ratio differently. As shown for amoxicillin, this can cause more confusion than certainty for globally operating companies. Harmonization of BCS guidelines is highly desirable.

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Toward Global Standards for Comparator Pharmaceutical Products: Case Studies of Amoxicillin, Metronidazole, and Zidovudine in the Americas

Cited by 32 publications

References 10 publications

Comparing the Dissolution Profiles of Seven Metformin Formulations in Simulated Intestinal Fluid

Comparing the Dissolution Profiles of Seven Metformin Formulations in Simulated Intestinal Fluid

Investigating the Dissolution Profiles of Amoxicillin, Metronidazole, and Zidovudine Formulations used in Trinidad and Tobago, West Indies

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

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