USP Apparatus 4: a Valuable In Vitro Tool to Enable Formulation Development of Long-Acting Parenteral (LAP) Nanosuspension Formulations of Poorly Water-Soluble Compounds

Abstract

Long-acting or extended release parenteral dosage forms have attracted extensive attention due to their ability to maintain therapeutic drug concentrations over long periods of time and reduce administration frequency, thus improving patient compliance. It is essential to have an in vitro release (IVR) testing method that can be used to assure product quality during routine production as well as predict and understand the in vivo performance of a formulation. The purpose of this work was to develop a discriminatory in vitro release method to guide formulation and process development of long-acting parenteral (LAP) nanosuspension formulations composed of poorly water-soluble drugs (BCS class II). Injectable nanosuspension formulations were developed to serve as test articles for method development. Several different IVR methods were evaluated for their application to the formulation screening and process development including (1) USP apparatus 2, (2) dialysis and reverse dialysis sac, and (3) continuous flow-through cell (USP apparatus 4). Preliminary data shows the promising results to support the utilization of USP 4 over more widely accepted USP 2 and dialysis methods. A combination of more representative in vivo hydrodynamics and ease of maintaining sink conditions yields the USP 4 flow-through cell method a more suitable in vitro release method for nanosuspension-based LAP formulations of poorly water-soluble compounds, such as compounds A and B.

Recent Progress in Drug Release Testing Methods of Biopolymeric Particulate System

“…For CF method, United States Pharmacopeia (USP) apparatus IV is recommended and many applications for in vitro drug release test of particulate formulations have been reported [ 67 , 68 , 69 , 70 , 71 , 72 ]. Originally, the USP apparatus IV was developed for in vitro dissolution testing of modified release oral dosage forms, but the diversity of flow-through cell types and the flexibility of medium volume allow it to be applied to a wide range of dosage forms [ 73 , 74 ].…”

“…The amount of drug released can be monitored online by a UV-Vis spectrophotometer or fiber optic probe, or samples can be collected in fractions and analyzed by HPLC or other appropriate method [ 64 , 65 , 69 , 70 , 71 , 72 , 73 ]. In particular, the fiber optic UV probe facilitates in situ monitoring of drug release from the microparticles while minimizing detection error due to interference of suspended microparticles and air bubbles caused by stirring [ 15 ].…”

Formulation Development and Evaluation of Injectable Depot Suspension

“…Transfer 1000 µl of MPA injectable suspension with the help of micropipette on glass bead in flow through cell (volume: 14 mL). Fix the assembly and set the pump flow [26] (16 ml/min) and temperature 37 o C [26]. Then run the apparatus as per dissolution parameters reported in Table 5 and Collect the sample at given time intervals.…”

“…Retention time: About 8.5 min for MPA, Run time:15 minute column: Syncronis C18150 x 4.6 mm, 5.0 µm, flow rate: 1.4 ml/min, Mobile phase for isocratic flow (Water/Acetonitrile 40/60), Diluent: 0.35% SLS) [26]. …”

Formulation development and evaluation of medroxyprogesterone acetate injectable suspension

“…In-vitro dissolution test was carried out by using USP type-IV apparatus (Flow through cell) 9 . 900 mL of pH 7.4 phosphate buffer and 0.50 % SLS was used as dissolution medium.…”