Solidification and oral delivery of biologics to the colon- A review.

The oral delivery of biologics such as therapeutic proteins, peptides and oligonucleotides for the treatment of colon related diseases has been the focus of increasing attention over the last years. However, the major disadvantage of these macromolecules is their degradation propensity in liquid state which can lead to the undesirable and complete loss of function. Therefore, to increase the stability of the biologic and reduce their degradation propensity, formulation techniques such as solidification can be performed to obtain a stable solid dosage form for oral administration. Due to their fragility, stress exerted on the biologic during solidification has to be reduced with the incorporation of stabilizing excipients into the formulation. This review focuses on the state-of-the-art solidification techniques required to obtain a solid dosage form for the oral delivery of biologics to the colon and the use of suitable excipients for adequate stabilization upon solidification. The solidifying processes discussed within this review are spray drying, freeze drying, bead coating and also other techniques such as spray freeze drying, electro spraying, vacuum- and supercritical fluid drying. Further, the colon as site of absorption in both healthy and diseased state is critically reviewed and possible oral delivery systems for biologics are discussed.

In-line solid state prediction during pharmaceutical hot-melt extrusion in a 12 mm twin screw extruder using Raman spectroscopy.

The aim of this research was to use Raman spectroscopy for the in-line monitoring of the solid state of materials during pharmaceutical hot-melt extrusion in the die head of a 12 mm (development scale) twin-screw extruder during formulation development. A full factorial (mixed) design was generated to determine the influence of variations in concentration of Celecoxib (CEL) in Eudragit® E PO, three different screw configurations and varying barrel temperature profiles on the solid state, 'melt temperature' and die pressure of continuously produced extrudates in real-time. Off-line XRD and DSC analysis were used to evaluate the suitability of Raman spectroscopy for solid state predictions. First, principal component analysis (PCA) was performed on all in-line collected Raman spectra from the experimental design. The resulting PC 1 versus PC 2 scores plot showed clustering according to solid state of the extrudates, and two classes, one class where crystalline CEL is still present and a second class where no crystalline CEL was detected, were found. Then, a soft independent modelling of class analogy (SIMCA) model was developed, by modelling these two classes separately by disjoint PCA models. These two separate PCA models were then used for the classification of new produced extrudates and allowed distinction between glassy solid solutions of CEL and crystalline dispersions of CEL. All extrudates were classified similarly by Raman spectroscopy, XRD and DSC measurements, with exception of the extrudates with a 30% CEL concentration extruded at 130 °C. The Raman spectra of these experiments showed bands which were sharper than the amorphous spectra, but broader than the crystalline spectra, indicating the presence of CEL that has dissolved into the matrix and CEL in its crystalline state. XRD and DSC measurements did not detect this. Modifications in the screw configuration did not affect the solid state and did not have an effect on the solid state prediction of new produced extrudates. Secondly, the influence of variations in die pressure on the Raman spectra was examined. The applied drug concentration, processing temperature and feeder performance influence the die pressure, which is reflected in the Raman spectra as a change in spectral intensity. When applying PCA on the raw spectra from the experimental design, the first principal component describes the influence of die pressure on the spectra, which was seen as a decrease in Raman intensity of the whole spectrum when the pressure in the sample increased. Clustering according to processing temperature was found, although the temperature in the die remained constant, indicating that a difference in viscosity, resulting in a changed die pressure, was detected. When the feeder was stopped, the score values of the first principal component almost simultaneously decreased, and only stabilized once the die pressure became stable. Since Raman spectra collected in the extrusion die are influenced by changes in die pressure, disturbances upstream of the extrusion process can be observed and identified in the Raman measurements.

Formulation of itraconazole nanococrystals and evaluation of their bioavailability in dogs.

The aim of the study is to increase the bioavailability of itraconazole (ITRA) using nanosized cocrystals prepared via wet milling of ITRA in combination with dicarboxylic acids. Wet milling was used in order to create a nanosuspension of ITRA in combination with dicarboxylic acids. After spray-drying and bead layering, solid state was characterized by MDSC, XRD, Raman and FT-IR. The release profiles and bioavailability of the nanococrystalline suspension, the spray-dried and bead layered formulation were evaluated. A monodisperse nanosuspension (549±51nm) of ITRA was developed using adipic acid and Tween®80. Solid state characterization indicated the formation of nanococrystals by hydrogen bounds between the triazole group of ITRA and the carboxyl group of adipic acid. A bioavailability study was performed in dogs. The faster drug release from the nanocrystal-based formulation was reflected in the in vivo results since Tmax of the formulations was obtained 3h after administration, while Tmax of the reference formulation was observed only 6h after administration. This fast release of ITRA was obtained by a dual concept: manufacturing of nanosized cocrystals of ITRA and adipic acid via wet milling. Formation of stable nanosized cocrystals via this approach seems a good alternative for amorphous systems to increase the solubility and obtain a fast drug release of BCS class II drugs.

Process monitoring and visualization solutions for hot-melt extrusion: a review.

OBJECTIVES: Hot-melt extrusion (HME) is applied as a continuous pharmaceutical manufacturing process for the production of a variety of dosage forms and formulations. To ensure the continuity of this process, the quality of the extrudates must be assessed continuously during manufacturing. The objective of this review is to provide an overview and evaluation of the available process analytical techniques which can be applied in hot-melt extrusion. KEY FINDINGS: Pharmaceutical extruders are equipped with traditional (univariate) process monitoring tools, observing barrel and die temperatures, throughput, screw speed, torque, drive amperage, melt pressure and melt temperature. The relevance of several spectroscopic process analytical techniques for monitoring and control of pharmaceutical HME has been explored recently. Nevertheless, many other sensors visualizing HME and measuring diverse critical product and process parameters with potential use in pharmaceutical extrusion are available, and were thoroughly studied in polymer extrusion. The implementation of process analytical tools in HME serves two purposes: (1) improving process understanding by monitoring and visualizing the material behaviour and (2) monitoring and analysing critical product and process parameters for process control, allowing to maintain a desired process state and guaranteeing the quality of the end product. SUMMARY: This review is the first to provide an evaluation of the process analytical tools applied for pharmaceutical HME monitoring and control, and discusses techniques that have been used in polymer extrusion having potential for monitoring and control of pharmaceutical HME.

Visualization and process understanding of material behavior in the extrusion barrel during a hot-melt extrusion process using Raman spectroscopy.

The aim of this research was to improve understanding of material behavior in pharmaceutical hot-melt extrusion by implementing a Raman probe in each section of the barrel. Fourier-transform infrared spectroscopy measurements were performed to confirm the Raman observations. Metoprolol tartrate (MPT) concentration (10 and 40% in Eudragit RSPO), extrusion temperature (100, 120, and 140 °C), and screw speed (80 and 160 rpm) were varied to examine their influence on polymer-drug solid state throughout the barrel. When extruding a formulation with a 40% MPT concentration, the broadening of MPT peaks indicates melting of MPT between sections 2 and 3, caused by the first kneading zone. Decreasing the concentration to 10% shows an additional spectral difference (i.e., peak shifts indicating interactions between MPT and the carrier) between sections 5 and 6, due to formation of a solid solution. At a 10% MPT load, increasing the extrusion temperature does not influence the solid state or the barrel section where the final solid state is obtained. At a drug load of 40%, the solid state of the end product is reached further down the barrel when the temperature decreases. Doubling the screw speed when processing a 10% MPT formulation does not affect the solid state of the product or the location where it is obtained. In contrast, at a 40% drug load, the section where the final product is produced, is situated earlier in the barrel, when applying a higher speed. The Raman spectra provide real-time information about polymer-drug behavior throughout the barrel, facilitating process understanding and optimization.

In-line NIR spectroscopy for the understanding of polymer-drug interaction during pharmaceutical hot-melt extrusion.

The aim was to evaluate near-infrared spectroscopy for the in-line determination of the drug concentration, the polymer-drug solid-state behaviour and molecular interactions during hot-melt extrusion. Kollidon® SR was extruded with varying metoprolol tartrate (MPT) concentrations (20%, 30% and 40%) and monitored using NIR spectroscopy. A PLS model allowed drug concentration determination. The correlation between predicted and real MPT concentrations was good (R(2)=0.97). The predictive performance of the model was evaluated by the root mean square error of prediction, which was 1.54%. Kollidon® SR with 40% MPT was extruded at 105°C and 135°C to evaluate NIR spectroscopy for in-line polymer-drug solid-state characterisation. NIR spectra indicated the presence of amorphous MPT and hydrogen bonds between drug and polymer in the extrudates. More amorphous MPT and interactions could be found in the extrudates produced at 135°C than at 105°C. Raman spectroscopy, DSC and ATR FT-IR were used to confirm the NIR observations. Due to the instability of the formulation, only in-line Raman spectroscopy was an adequate confirmation tool. NIR spectroscopy is a potential PAT-tool for the in-line determination of API concentration and for the polymer-drug solid-state behaviour monitoring during pharmaceutical hot-melt extrusion.

Detection of counterfeit Viagra® by Raman microspectroscopy imaging and multivariate analysis.

During the past years, pharmaceutical counterfeiting was mainly a problem of developing countries with weak enforcement and inspection programs. However, Europe and North America are more and more confronted with the counterfeiting problem. During this study, 26 counterfeits and imitations of Viagra® tablets and 8 genuine tablets of Viagra® were analysed by Raman microspectroscopy imaging. After unfolding the data, three maps are combined per sample and a first PCA is realised on these data. Then, the first principal components of each sample are assembled. The exploratory and classification analysis are performed on that matrix. PCA was applied as exploratory analysis tool on different spectral ranges to detect counterfeit medicines based on the full spectra (200-1800 cm⁻¹), the presence of lactose (830-880 cm⁻¹) and the spatial distribution of sildenafil (1200-1290 cm⁻¹) inside the tablet. After the exploratory analysis, three different classification algorithms were applied on the full spectra dataset: linear discriminant analysis, k-nearest neighbour and soft independent modelling of class analogy. PCA analysis of the 830-880 cm⁻¹ spectral region discriminated genuine samples while the multivariate analysis of the spectral region between 1200 cm⁻¹ and 1290 cm⁻¹ returns no satisfactory results. A good discrimination of genuine samples was obtained with multivariate analysis of the full spectra region (200-1800 cm⁻¹). Application of the k-NN and SIMCA algorithm returned 100% correct classification during both internal and external validation.