Prediction of drug dissolution from Toremifene 80 mg tablets by NIR spectroscopy

The aim of our study was to justify substitution of dissolution analysis for NIR measurement of Toremifene 80 mg tablets. We studied implementation of a NIRS method by integrating the method development to discrimination power of the dissolution method. Hence, we analyzed 20 DoE tablet batches and studied which of the critical formulation factors affecting dissolution were statistically significant. To study if these factors can be detected by NIRS, PLS calibration models were developed. Finally, PLS model was built to correlate NIR data with the actual dissolution results to predict the released amount of toremifene in 30 min. To obtain the data the tablet batches were measured by NIR using diffuse reflectance technique and multivariate analysis tool was used to calibrate the NIRS models. Correlations between the critical formulation factors and the NIR spectra of Toremifene 80 mg tablet were shown and it was thus justified to develop a NIRS prediction model for dissolution. Variance (R-2), standard error of estimate (SEE) and standard error of prediction (SEP) of the model were 90.0%, 4.3% and 5.9%, respectively. It was thus shown that mull-phased and time consuming dissolution procedure could be substituted for fast non-invasive NIRS method.Peer reviewe

Clinical Relevance of Dissolution Testing in Quality by Design

Quality by design (QbD) has recently been introduced in pharmaceutical product development in a regulatory context and the process of implementing such concepts in the drug approval process is presently on-going. This has the potential to allow for a more flexible regulatory approach based on understanding and optimisation of how design of a product and its manufacturing process may affect product quality. Thus, adding restrictions to manufacturing beyond what can be motivated by clinical quality brings no benefits but only additional costs. This leads to a challenge for biopharmaceutical scientists to link clinical product performance to critical manufacturing attributes. In vitro dissolution testing is clearly a key tool for this purpose and the present bioequivalence guidelines and biopharmaceutical classification system (BCS) provides a platform for regulatory applications of in vitro dissolution as a marker for consistency in clinical outcomes. However, the application of these concepts might need to be further developed in the context of QbD to take advantage of the higher level of understanding that is implied and displayed in regulatory documentation utilising QbD concepts. Aspects that should be considered include identification of rate limiting steps in the absorption process that can be linked to pharmacokinetic variables and used for prediction of bioavailability variables, in vivo relevance of in vitro dissolution test conditions and performance/interpretation of specific bioavailability studies on critical formulation/process variables. This article will give some examples and suggestions how clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for a BCS II compound

Multi-drug-loaded Microcapsules with Controlled Release for Management of Parkinson's Disease

Parkinson's disease (PD) is a progressive disease of the nervous system, and is currently managed through commercial tablets that do not sufficient enable controlled, sustained release capabilities. It is hypothesized that a drug delivery system that provides controlled and sustained release of PD drugs would afford better management of PD. Hollow microcapsules composed of poly-L-lactide (PLLA) and poly (caprolactone) (PCL) were prepared through a modified double-emulsion technique. They were loaded with three PD drugs, i.e. levodopa (LD), carbidopa (CD) and entacapone (ENT), at a ratio of 4:1:8, similar to commercial PD tablets. LD and CD were localized in both the hollow cavity and PLLA/PCL shell, while ENT was localized in the PLLA/PCL shell. Release kinetics of hydrophobic ENT was observed to be relatively slow as compared to the other hydrophilic drugs. It was further hypothesized that encapsulating ENT into PCL as a surface coating onto these microcapsules can aid in accelerating its release. Now, these spray-coated hollow microcapsules exhibited similar release kinetics, according to Higuchi’s rate, for all three drugs. The results suggest that multiple drug encapsulation of LD, CD and ENT in gastric floating microcapsules could be further developed for in vivo evaluation for the management of PD.ASTAR (Agency for Sci., Tech. and Research, S’pore)NMRC (Natl Medical Research Council, S’pore)MOH (Min. of Health, S’pore)Accepted versio

Preparation and In Vitro/In Vivo Evaluation of Microparticle Formulations Containing Meloxicam

In this study, we have formulated chitosan-coated sodium alginate microparticles containing meloxicam (MLX) and aimed to investigate the correlation between in vitro release and in vivo absorbed percentages of meloxicam. The microparticle formulations were prepared by orifice ionic gelation method with two different sodium alginate concentrations, as 1% and 2% (w/v), in order to provide different release rates. Additionally, an oral solution containing 15 mg of meloxicam was administered as the reference solution for evaluation of in vitro/in vivo correlation (ivivc). Following in vitro characterization, plasma levels of MLX and pharmacokinetic parameters [elimination half-life (t (1/2)), maximum plasma concentration (C (max)), time for C (max) (t (max))] after oral administration to New Zealand rabbits were determined. Area under plasma concentration-time curve (AUC(0-a)) was calculated by using trapezoidal method. A linear regression was investigated between released% (in vitro) and absorbed% (in vivo) with a model-independent deconvolution approach. As a result, increase in sodium alginate content lengthened in vitro release time and in vivo t (max) value. In addition, for ivivc, linear regression equations with r (2) values of 0.8563 and 0.9402 were obtained for microparticles containing 1% and 2% (w/v) sodium alginate, respectively. Lower prediction error for 2% sodium alginate formulations (7.419 +/- 4.068) compared to 1% sodium alginate formulations (9.458 +/- 5.106) indicated a more precise ivivc for 2% sodium alginate formulation.Wo