Development of a Single In Vitro Dissolution Method for a Combination Trilayer Tablet Formulation of Clopidogrel and Pravastatin

Abstract

A fixed-combination dose, trilayer tablet formulation was developed for two drugs already marketed as individual products, Plavix in which clopidogrel, an anti-clotting agent, is the active ingredient and pravastatin, an HMG-CoA reductase inhibitor for the treatment of hypercholesterolemia. To simplify quality control testing, the preference is to use a single dissolution method for the analysis of multiple active components in a combination tablet. However, development of one dissolution method for clopidogrel and pravastatin is particularly challenging because of the divergent pH solubility and pH dependent stability of these two drugs. At low pH (<3), clopidogrel bisulfate is most soluble and stable, whereas pravastatin sodium rapidly degrades due to lactonization and oxidation. Conversely, at a neutral pH and higher, pravastatin sodium is most soluble and stable, but clopidogrel bisulfate undergoes hydrolysis and racemization. This article describes the development of a single dissolution method to accommodate both drugs, including selection of medium pH and surfactant. The method uses USP Apparatus 2 (paddles) at 75 rpm in 1000 mL of citrate buffer (0.05 M, pH 5.5) medium containing 2% CTAB (cetyltrimethyl ammonium bromide, a cationic surfactant) at 37 °C. This dissolution methodology provides good dissolution profiles for both clopidogrel and pravastatin and is able to discriminate the changes in composition, manufacturing process, and stability for the combination tablets. To quantitate both drugs simultaneously, a rapid isocratic reversed-phase liquid chromatographic method was developed and validated.

An Assessment of Occasional Bio-Inequivalence for BCS1 and BCS3 Drugs: What are the Underlying Reasons?

“…Similarly, pravastatin has been reported to be vulnerable to rapid gastric degradation 76 . For instance, significant degradation within in-vivo relevant time frames at pH 3.0 / 40⁰C have been reported 77 .…”

“…For the pravastatin BE failure example, Cmax is altered, but AUC is unchanged. In the detailed study by Ruiz-Picazo et al 28 on pravastatin BE failure, the potential for gastric degradation as a contribution to BE failure is not mentioned, although it has been reported elsewhere that generation of low pH dissolution data was not possible as a result of the degradation kinetics 76 . The propensity of pravastatin for gastric degradation is the likely explanation for the marked difference in the reported solubility values at pH1.2 in these two papers, and may have compromised the ability of the dissolution test to detect differences between the formulations studied by Ruiz-Picazo et al 28 .…”

Apixaban and clopidogrel in a fixed-dose combination: Formulation and in vitro evaluation

“…Many formulations were developed later in different dosage forms to enhance CLOP solubility and bioavailability. A literature search revealed formulating CLOP as IR tablets ( Kavya et al, 2014 , Kumar et al, 2013 ), gastro retentive system as floated tablets ( Rao and Lakshmi, 2014 ), high-density tablets ( Desai and Purohit, 2017 ) or floated osmotic capsules ( Shah and Prajapati, 2019 ), liquisolid compact ( Ali et al, 2021 , Mohammed and Mohammed, 2018 ), micro-emulsion ( Patel et al, 2010 ), nano-suspension ( Jassim and Hussein, 2014 ), oral disintegrating tablets ( Mahrous et al, 2016 ), or fast disintegrating films (Alladi Saritha, 2018 ), and as FDC system ( Huang et al, 2011 , Seo and Han, 2019 ).…”

Formulation and Optimization of Floating Tablets of Clopidogrel Bisulphate Using Design of Experiments

“…Although not completely understood, the variability in the antiplatelet effect of clopidogrel is attributed to its variable gastrointestinal absorption which is a result of low solubility [10]. The solubility of clopidogrel is mainly reported to be pH dependent, showing higher solubility in acidic pH and solubility drops when pH increases above 3.0 [11]. Taking this into account, a gastroretentive drug delivery system, releasing the maximum drug in acidic stomach pH would be desirable.…”