A Flow Imaging Microscopy-Based Method Using Mass-to-Volume Ratio to Derive the Porosity of PLGA Microparticles.

The release of drugs from poly(lactic-co-glycolic acid) (PLGA) microparticles depends to a large extent on the porosity of the particles. Therefore, porosity determination of PLGA microparticles is extremely important during pharmaceutical product development. Currently, mercury intrusion porosimetry (MIP) is widely used despite its disadvantages, such as the need for a large amount of sample (several hundreds of milligrams) and residual toxic waste. Here, we present a method based on the estimation of the volume of a known mass (a few milligrams) of particles using micro-flow imaging (MFI) to determine microparticle batch porosity. Factors that are critical for the accuracy of this method (i.e., density of the suspending fluid, particle concentration, and postsample rinsing) were identified and measures were taken to minimize potential errors. The validity of the optimized method was confirmed by using nonporous polymethylmethacrylate microparticles. Finally, the method was employed for the analysis of 7 different PLGA microparticle batches with various porosities (4.0%-51.9%) and drug loadings (0%-38%). Obtained porosity values were in excellent agreement with the MIP-derived porosities. Altogether, the developed MFI-based method is a valuable tool for deriving the total volume of a known mass of PLGA particles and therewith their porosity.

Micro-Flow Imaging as a quantitative tool to assess size and agglomeration of PLGA microparticles.

The purpose of this study was to explore the potential of flow imaging microscopy to measure particle size and agglomeration of poly(lactic-co-glycolic acid) (PLGA) microparticles. The particle size distribution of pharmaceutical PLGA microparticle products is routinely determined with laser diffraction. In our study, we performed a unique side-by-side comparison between MFI 5100 (flow imaging microscopy) and Mastersizer 2000 (laser diffraction) for the particle size analysis of two commercial PLGA microparticle products, i.e., Risperdal Consta and Sandostatin LAR. Both techniques gave similar results regarding the number and volume percentage of the main particle population (28-220µm for Risperdal Consta; 16-124µm for Sandostatin LAR). MFI additionally detected a 'fines' population (<28µm for Risperdal Consta; <16µm for Sandostatin LAR), which was overlooked by Mastersizer. Moreover, MFI was able to split the main population into 'monospheres' and 'agglomerates' based on particle morphology, and count the number of particles in each sub-population. Finally, we presented how MFI can be applied in process development of risperidone PLGA microparticles and to monitor the physical stability of Sandostatin LAR. These case studies showed that MFI provides insight into the effect of different process steps on the number, size and morphology of fines, monospheres and agglomerates as well as the extent of microparticle agglomeration after reconstitution. This can be particularly important for the suspendability, injectability and release kinetics of PLGA microparticles.

A phase 0 clinical trial of novel candidate extended-release formulations of capecitabine.

PURPOSE: To examine the pharmacokinetic (PK) profile of several candidate extended-release (ER) formulations of capecitabine in patients. METHODS: In a phase 0 clinical study, PK profiles of several oral candidate ER formulations of capecitabine were compared to the PK profile of capecitabine after administration of the commercially available immediate-release (IR) tablet. A single dose of 1000 mg IR formulation (two 500 mg tablets) was administered on day 1, and a single dose of a 1000 mg candidate ER formulation of capecitabine (two 500 mg tablets) was administered on day 2. Candidate ER formulations of capecitabine differed with regard to the amount of the ER excipient (Kollidon(®) SR) in tablet matrix (0-5 % w/w) and coating (0-12 mg/cm(2)). RESULTS: PK profiles of nine different candidate ER formulations were examined. The tablet coating seemed the main determinant for ER of capecitabine and tablet integrity. Average (±standard deviation) AUC0-2h, relative to AUC0-2h after oral administration of the IR tablet, were 43.3 % (±34.9 %) and 1.2 % (±1.2 %) for candidate ER formulations coated with 3 and 6 mg/cm(2), respectively. Corresponding AUC0-last were 93.6 % (±40.2 %) and 44.0 % (±5.4 %). CONCLUSION: Modulation of capecitabine release in patients can be accomplished by varying tablet coating content. Proof of principle was demonstrated for candidate ER formulations with coating content of 3 mg/cm(2).

Development of an extended-release formulation of capecitabine making use of in vitro-in vivo correlation modelling.

An oral extended-release (ER) formulation of capecitabine was developed for twice daily dosing, theoretically providing a continuous exposure to capecitabine, thus avoiding the undesirable in-between dosing gap inherent to the dosing schedule of the marketed capecitabine immediate-release formulation (Xeloda(®)). The target 12-hour in vivo release profile was correlated to an in vitro dissolution profile using an in vitro-in vivo correlation model based on the pharmacokinetic (PK) and dissolution characteristics of Xeloda(®). Making use of the slow dissolution characteristics of amorphous capecitabine as reported previously and screening of a panel of ER excipients, an ER formulation was designed. Kollidon(®) SR induced the most prominent ER. Moreover, it was shown that tablets prepared from CoSD capecitabine and Kollidon(®) SR have an additional threefold delay in dissolution compared with tablets prepared from the same but only physically mixed components. Therefore, a prototype tablet formulation composed of co-spray-dried capecitabine and Kollidon(®) SR (98/2%, w/w) mixed with colloidal silicon dioxide (0.5%, w/w) and magnesium stearate (2.5%, w/w) was defined. This prototype shows similar dissolution characteristics as the modelled dissolution profile. Currently, the in vivo PK of our designed ER capecitabine formulations is investigated in a clinical study.

Slow dissolution behaviour of amorphous capecitabine.

In this article, we report the anomalous dissolution behaviour of amorphous capecitabine. In contrast to what is expected from thermodynamic theory, amorphous capecitabine dissolves significantly slower compared to its crystalline counterpart. Our experiments show that this is due to the "gelling" properties of amorphous capecitabine in an aqueous environment. The "gel", which is immediately formed upon contact with water, entraps the capecitabine and significantly slows down its dissolution. This "gelling" property is hypothesized to be related to the low glass transition temperature (Tg 19°C) of amorphous capecitabine, resulting in an instant collapse ("gelling") in an aqueous environment. From IR and DSC analysis it is shown that this collapsed capecitabine is remarkably stable and does not recrystallize upon an increased water content or temperature. This highly reproducible dissolution behaviour can be applied in the development of a sustained release dosage form as substantially less sustained release excipient is required in order to attain the desired release profile. As capecitabine is a high-dosed drug, this is highly favourable in view of the size and thus clinical feasibility of the final dosage form. Currently, we are developing and clinically testing a sustained release formulation making use of amorphous capecitabine and its remarkable dissolution behaviour.