Model Drug as Pore Former for Controlled Release of Water-Soluble Metoprolol Succinate from Ethylcellulose-Coated Pellets Without Lag Phase: Opportunities and Challenges

Abstract

Abstract. The objective of the present study was to evaluate the feasibility of using model drug metoprolol succinate (MS) as a pore former to modify the initial lag phase (i.e., a slow or non-release phase in the first 1-2 h) associated with the drug release from coated pellets. MS-layered cores with high drug-layering efficiency (97% w/w) were first prepared by spraying a highly concentrated drug aqueous solution (60% w/w, 70°C) on non-pareils without using other binders. The presence of MS in ethylcellulose (EC) coating solution significantly improved the coating process by reducing pellets sticking, which often occurs during organic coating. There may be a maximum physical compatibility of MS with EC, and the physical state of the drug in the functional coating layer of EC/MS (80:20) was simultaneously crystalline and noncrystalline (amorphous or solid molecule solution). The lag phase associated with hydroxypropylcellulose (HPC) as a pore former was not observed when MS was used as a pore former. The drug release from EC/ MS-coated pellets was pH independent, inversely proportional to the coating levels, and directly related to the pore former levels. The functional coating layer with MS as a pore former was not completely stabilized without curing. Curing at 60°C for 1 day could substantially improve the stability of EC/MScoated pellets. The physical state of the drug in the free film of EC/MS (85:15) changed partially from amorphous to crystal when cured at 60°C for 1 day, which should be attributed to the incompatibility of the drug with EC.

An emerging terpolymeric nanoparticle pore former as an internal recrystallization inhibitor of celecoxib in controlled release amorphous solid dispersion beads: Experimental studies and molecular dynamics analysis

“…The issue of supersaturation and precipitation is especially problematic at lower pore former concentrations, where a lack of interconnections ( i.e. , failure to percolate) to form continuous channels could result in isolated, ill-defined passageways and further impede drug release 34 , 45 .…”

“…Compared to conventional, water soluble polymeric pore formers, TPN resulted in lower viscosity of coating suspension, higher film integrity, homogenous distribution in the film and negligible leaching as a pore former in ethylcellulose (EC) coatings due to its miscibility in suspension and structural compatibility with EC 32 . Rather than forming water-filled channels for drug diffusion by leaching out 33 , 34 , TPN remains embedded within the membrane, maintaining nano-scale pores formed by its swelling upon hydration 32 . Hence in this work, we investigate for the first time whether the sustained, nanoscaled pores of TPN, its enduring presence within an EC membrane as a unique performer, and potential molecular interaction with model drug, celecoxib (CEL), would enable the CRASD bead design to prolong amorphicity, prevent onset of recrystallization within the dosage form, and improve the attainable extent of drug release.…”

Independent Tailoring of Dose and Drug Release via a Modularized Product Design Concept for Mass Customization

“…(iia) Increase the total number of dosage form release profiles within a given range (through fine-tuning): Current academic research on individualized release predominantly utilizes a fine-tuning approach as a means to improve drug release flexibility, whereby modification of one release-determining structural feature allows tuning of drug release iteratively, on a continuous scale, and which confines variety in release profiles to variants of the same release profile shape or mechanism. Examples include modifying shell thickness in core–shell designs to prolong or shorten lag times [ 85 , 87 ], modifying porosity or the exposed surface area to obtain faster or slower kinetics with the same release profile shape [ 88 , 89 , 90 ], and so forth. This is also attainable with our product concept, for example, by modifying the exposed surface area of MV1 (as shown in Figure 6 ), modifying lid thickness of MV2 to achieve different lag times, or reducing orifice size of MV3 to achieve slower initial drug release kinetics.…”

“…Subsequent translation to robust performance needs to be ensured. Beyond the smallest orifice size that can be printed with high precision, alternative approaches such as porous materials achieved though mixtures of water-insoluble polymers with water-soluble pore formers already exist [ 60 , 83 , 90 , 91 , 92 ]. This can not only provide fine-tuning as necessary for individualization but also expands the range of accessible release profiles as described above.…”

Aqueous Film Coating the Current Trend

“…coat, as to control the diffusion/release of drug(s) from substrate core. For instance sodium chloride or sucrose with EC-coated tablets of salicylic acid 56,57 .…”