Identification and Characterization of Rotigotine Degradation Products by HPLC Coupled DAD and CAD Detectors and HRMS Through Q-Orbitrap and Electrospray Ionization.

Rotigotine (RTG) is a dopamine agonist used in the treatment of Parkinson's disease. As it is susceptible to oxidation, stability studies must be carefully designed for the identification and characterization of all possible degradation products. Here, RTG degradation was evaluated according to the International Conference on Harmonization guidelines under various stress conditions, including acidic and basic hydrolysis, oxidative, metallic, photolytic, and thermal conditions. Additionally, more severe stress conditions were applied to induce RTG degradation. Significant degradation was only observed under oxidative and photolytic conditions. The samples were analyzed by high performance liquid chromatography coupled to photodiode array detectors, charged aerosol, and high-resolution mass spectrometry. Chromatographic analyses revealed the presence of eight substances related to RTG, four of which were already described and were qualified impurities (impurities B, C, K and E) and four new degradation products (DP-1 - DP-4), whose structures were characterized by high-resolution mass spectrometry through Q-Orbitrap and electrospray ionization. In the stress testing of the active pharmaceutical ingredient in solid form, significant RTG degradation was observed in the presence of the oxidative matrix. The results corroborate the literature that confirm the high susceptibility of RTG to oxidation and the importance of using different detectors to detect degradation products in forced degradation studies.

Rotigotine: A Review of Analytical Methods for the Raw Material, Pharmaceutical Formulations, and Its Impurities.

BACKGROUND: Rotigotine is a dopaminergic agonist developed for the treatment of Parkinson's disease and restless leg syndrome. The pure levorotatory enantiomer is marketed in several countries as a transdermal patch. Reports of oxidation and instability in a previous formulation indicate the need to evaluate impurities in both the raw material and pharmaceutical dosage forms of rotigotine to ensure product quality. OBJECTIVE: This review examines the main analytical methods for analyzing rotigotine in raw material and its transdermal patches with the aim of assisting the development of new pharmaceutical formulations and stability studies. METHODS: Analytical methods based on high-performance liquid chromatography for rotigotine from pharmacopoeias and literature were evaluated. A comparison was made between the methods found in the literature and official rotigotine monographs described by the United States, European, and British Pharmacopoeias, including a discussion of their acceptance limits for impurities related to the drug. The different impurities from the synthesis processes and degradation studies of rotigotine were also evaluated, as well as the main articles that describe methods for assessing their chiral purity. RESULTS: Qualified and unofficial official impurities found in forced degradation studies were verified. The methods presented show adequate specificity and selectivity in determining the drug in the presence of its impurities. CONCLUSIONS: The approached methods are promising, but more detailed studies on the stability of rotigotine are still lacking, mainly in the pharmacokinetic and toxicological characterization of its impurities.

Development of USP Apparatus 3 Dissolution Method with IVIVC for Extended Release Tablets of Metformin Hydrochloride and Development of a Generic Formulation.

Metformin is a euglycemic drug for the treatment of type 2 diabetes mellitus. To date, there are 13 dissolution methodologies described in the U.S. Pharmacopoeia (USP) to evaluate the release profile of metformin from extended-release tablets utilizing either a USP apparatus 1 (basket) or 2 (paddle). In the absence of a protocol for a USP apparatus 3 (reciprocating cylinder), the goal of this work was to develop an in vitro dissolution method for metformin extended-release tablets based on an in vivo-in vitro correlation (IVIVC). Following a systematic evaluation, a final dissolution method, M4, was defined. It applied 30 dips per minute (dpm) over a total period of 10 h into a series of solutions that included 2 h in HCl media (pH 1.2), 1 h in an acetate buffer solution (pH 4.5), 1 h in phosphate buffer solution (PBS) (pH 5.8) and 6 h in PBS (pH 6.8). This method showed a significant IVIVC with a calculated R2 > 0.98 (point-to-point correlation, Level A) and it was successfully used as a tool to assist in the development of generic extended release formulations for metformin consisting of a lipophilic matrix system.

Development and validation of a dissolution test for lutein tablets and evaluation of intestinal permeability.

Lutein is a carotenoid with antioxidant activity that is present in various dosage forms. The bioavailability of carotenoid from oral dosage formulations depends on their release, dissolution and its permeability through the gastrointestinal tract. Here, a dissolution test was developed for evaluating formulations and the bioavailability was assessed. The test utilized a USP-apparatus II with rotations of 50, 75 and 100rpm in water with P80 at 1, 2 and 5% (w/v). A non-everted rat intestinal sac model was used in conjunction to assess the intestinal permeability. The most discriminative conditions were 100rpm in water with 2% polysorbate 80, which showed profile differences between two formulations. The intestinal permeation studies showed a lag-time and apparent permeability coefficient that were characteristic of highly permeable drugs. We suggest that a dissolution test can be an essential quality control tool for formulations containing compounds as lutein, although not mandatory by the regulation agencies.