Preparation of Solifenacin Succinate Functional Particles Embedded in a Gelling-Swelling Layer (PEGS) and Their Formulation in Orally Disintegrating Tablets.

The purpose of this research was firstly to prepare solifenacin succinate functional particles embedded in a gelling-swelling layer (PEGS) so as to achieve both taste-masking of the unpleasant taste of the drug and rapid drug elution, and secondly to incorporate these PEGS into orally disintegrating tablets (ODTs). In in vitro dissolution tests, initial drug release from the prepared PEGS could be suppressed to less than 1% after 2 min and increased to more than 85% after 30 min by adjusting the composition of the PEGS, in particular the thickness of the outer water-penetration control layer which contains a water-insoluble polymer. For the preparation of ODTs containing PEGS, a semi-direct compression method was adopted in order to prevent damage to the PEGS by processes such as granulation or compaction. The use of a fibre-shaped microcrystalline cellulose with poor fluidity improved the content uniformity of the ODTs, as the crystal fibres became entangled with the PEGS and other additives. The use of spherical mannitol with a hollow structure produced by spray drying imparted relatively high hardness and rapid disintegration properties to the final ODTs containing PEGS, which were tableted using a low compression force. There was no significant difference in the drug-release profiles of the optimally formulated ODTs containing PEGS tableted at different compression forces. The ODTs containing PEGS maintained a drug-release lag time sufficient for taste-masking of solifenacin succinate.

Evaluation of in Vitro and in Vivo Transdermal Absorption of Solifenacin Succinate.

Solifenacin (Sol), an antimuscarinic agent has been widely used for the treatment of overactive bladder. Transdermal formulations can be administered without water as well as absorbed slowly into the blood over a long period of time. The aim of this study was to develop cream and tape formulations of Sol, and evaluate the transdermal permeation and absorption of the drug from the two formulations in vitro and in vivo, respectively. In the preparation of cream formulation, Sol succinate was dissolved in purified water, and the mixture was added to the hydrophilic cream. Then, aqueous sodium hydroxide was added to the cream. In the tape formulation, Sol succinate was dissolved in a solvent with propylene glycol, diisopropanolamine, triethyl citrate, and EUDRAGIT E100. The dissolved solvent was poured onto a polyethylene film. Cream (5%) and tape (15%) formulations demonstrated high skin permeability. Addition of an adsorption enhancer (N-methyl-2-pyrrolidone) did not further increase the level of skin permeability. In subsequent in vivo experiments in rats, both the cream and tape formulations led to slow absorption of Sol into plasma, with increased t1/2 compared with oral administration. Plasma Sol concentrations peaked 24 h after transdermal application and the drug was still detectable in plasma 72 h after application. Additionally, the cream (5%) and tape (15%) formulations resulted in a higher area under the plasma concentration vs. time curve from 0 to 72 h (AUC0-72) compared with oral formulation (30 mg/kg). In conclusion, significant in vitro permeability and in vivo absorption of Sol from the transdermal formulations were observed.

Enhanced spectrofluorimetric determination of two novel combination therapies for the treatment of benign prostatic hyperplasia containing tamsulosin hydrochloride.

Two novel combination therapies for the treatment of benign prostatic hyperplasia were analyzed using simple and enhanced spectrofluorimetric methods based on derivative and derivative ratio techniques. The two combinations contained tamsulosin hydrochloride (TAM) as a minor component with tolterodine tartrate (TOL) or solifenacin succinate (SOL). The fluorescence of the three drugs under study was measured in methanolic water solution. For the TAM and SOL mixture, successful resolution between both drugs was achieved by derivative manipulation of both ratio and zero-order emission spectra with good linearity in the ranges of 0.75-3.50 and 2.5-15.0 µg ml-1 for TAM and SOL, respectively. Extensive emission spectral overlap was observed for the TAM and TOL mixture. Therefore, only derivative application of the ratio emission spectra resolved such overlap and quantitated TAM and TOL simultaneously in the ranges 0.75-3.50 and 2.5-20.0 µg ml-1 for TAM and TOL, respectively. Optimization of various experimental parameters that affected the fluorescence intensity of the three drugs was performed. Successful application of all proposed methods was achieved for analysis of the two drugs in each combination therapy in their laboratory-prepared mixtures and dosage forms with good accuracy and precision.

Evaluation of Maltose-Induced Chemical Degradation at the Interface of Bilayer Tablets.

Fixed dose combination tablets consisting of mirabegron (MB) and solifenacin succinate (SS) were developed and formulated into bilayer tablets in the current study. The results of a chemical stability study showed that the original formulation for the tablets led to a significant increase of unknown degradants in the SS layer. Two compatibility studies were conducted to simulate the interface between the MB and SS layers, and the results revealed that the degradants only formed in the presence of both active pharmaceutical ingredients (APIs), and that the presence of maltose in the SS layer was critical to inducing degradation. High resolution mass spectroscopy coupled with high performance liquid chromatography was used to determine the chemical structures of the degradants, which were identified to MB derivatives bearing one or two sugar units. These findings therefore suggested that the degradation of the API could be attributed to the addition of sugar units from maltose to MB under the acidic conditions caused by SS. With this in mind, we developed a new formulation by replacing maltose with hydroxypropyl cellulose as a polymer-type binder. The results showed that this formulation suppressed the formation of the degradants. The results of this study have shown that chemical degradation can occur at the interface of bilayer tablets and that an alternative strategy is available to formulate more stable MB/SS bilayer tablets.

Bringing biocatalytic deuteration into the toolbox of asymmetric isotopic labelling techniques.

Enzymes dependent on nicotinamide cofactors are important components of the expanding range of asymmetric synthetic techniques. New challenges in asymmetric catalysis are arising in the field of deuterium labelling, where compounds bearing deuterium (2H) atoms at chiral centres are becoming increasingly desirable targets for pharmaceutical and analytical chemists. However, utilisation of NADH-dependent enzymes for 2H-labelling is not straightforward, owing to difficulties in supplying a suitably isotopically-labelled cofactor ([4-2H]-NADH). Here we report on a strategy that combines a clean reductant (H2) with a cheap source of 2H-atoms (2H2O) to generate and recycle [4-2H]-NADH. By coupling [4-2H]-NADH-recycling to an array of C=O, C=N, and C=C bond reductases, we demonstrate asymmetric deuteration across a range of organic molecules under ambient conditions with near-perfect chemo-, stereo- and isotopic selectivity. We demonstrate the synthetic utility of the system by applying it in the isolation of the heavy drug (1S,3'R)-[2',2',3'-2H3]-solifenacin fumarate on a preparative scale.

Quantitation of trace amorphous solifenacin succinate in pharmaceutical formulations by transmission Raman spectroscopy.

It is important to quantify amorphous solid in active pharmaceutical ingredients (API) of formulations to guarantee high-quality pharmaceutical products. In this study, we aimed to quantify amorphous solid in API by transmission Raman spectroscopy (TRS) and transmission near-infra-red spectroscopy (NIRS). To quantify the amount of trace amorphous solids contained in the API of a formulation, calibration curves of tablets containing 40% or 3% solifenacin succinate (SLFS) in the pharmaceutical formulations were prepared. The tablets varied in the ratio of amorphous solids in the API. TRS and NIRS were carried out with the calibration tablets and partial least square regression (PLSR) analysis was performed. Good results were obtained by both TRS and NIRS with the calibration model containing 40% SLFS. On the contrary, with the calibration model containing 3% SLFS, the PLSR analysis results using the TRS data were better than those using the NIRS data. The low content calibration model based on TRS showed good results with R2 of 0.999, RMSECV of 1.236, and LOD of 0.12. TRS can be used to specifically detect trace amorphous solids contained in the API of a formulation.