Lieven Baert

Characterization of solid dispersions of itraconazole and hydroxypropylmethylcellulose prepared by melt extrusion. Part I

Solid dispersions containing different ratios of itraconazole and hydroxypropylmethylcellulose (HPMC) were prepared by solvent casting. Based on dose, differential scanning calorimetry and dissolution results, a drug/polymer ratio of 40/60 w/w was selected in order to prepare dispersions by melt extrusion. The melt extrusion process was characterized using a design of experiments (DOE) approach. All parameter settings resulted in the formation of an amorphous solid dispersion whereby HPMC 2910 5 mPas prevents re-crystallization of the drug during cooling. Dissolution measurements demonstrated that a significantly increased dissolution rate was obtained with the amorphous solid dispersion compared to the physical mixture. The outcome of DOE further indicated that melt extrusion is very robust with regard to the itraconazole/HPMC melt extrudate characteristics. Stability studies demonstrated that the itraconazole/HPMC 40/60 w/w milled melt extrudate formulation is chemically and physically stable for periods in excess of 6 months as indicated by the absence of degradation products or re-crystallization of the drug.

Extrusion-spheronisation A literature review

Abstract This review article deals with the aspects of the extrusion-spheronisation process. The different steps in the production process of pellets are described. In a second part the parameters which can influence the pellet quality are discussed. Finally, an overview of the methods available for analysis of the quality of the pellets is given.

Development of a long-acting injectable formulation with nanoparticles of rilpivirine (TMC278) for HIV treatment

Long-acting parenteral formulations of antiretrovirals could facilitate maintenance and prophylactic treatment in HIV. Using the poorly water- and oil-soluble non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 (rilpivirine) as base or hydrochloride (HCl), nanosuspensions were prepared by wet milling (Elan NanoCrystal technology) in an aqueous carrier. Laser diffraction showed that the average particles size were (1) close to the targeted size proportionality (200-400-800 nm), with increasing distributions the larger the average particle size, and (2) were stable over 6 months. Following single-dose administration, the plasma concentration profiles showed sustained release of TMC278 over 3 months in dogs and 3 weeks in mice. On comparison of intramuscular and subcutaneous injection of 5mg/kg (200 nm) in dogs, the subcutaneous route resulted in the most stable plasma levels (constant at 25 ng/mL for 20 days, after which levels declined slowly to 1-3 ng/mL at 3 months); 200 nm nanosuspensions achieved higher and less variable plasma concentration profiles than 400 and 800 nm nanosuspensions. In mice, the pharmacokinetic profiles after a single 20mg/kg dose (200 nm) were similar with two different surfactants used (poloxamer 338, or d-alpha-tocopheryl polyethylene glycol 1000 succinate). In conclusion, this study provides proof-of-concept that 200-nm sized TMC278 nanosuspensions may act as long-acting injectable.

Pharmacokinetics and Disposition of Rilpivirine (TMC278) Nanosuspension as a Long-Acting Injectable Antiretroviral Formulation

ABSTRACT The next-generation human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitor rilpivirine (TMC278) was administered in rats and dogs as single intramuscular (IM) or subcutaneous (SC) injections, formulated as a 200-nm nanosuspension. The plasma pharmacokinetics, injection site concentrations, disposition to lymphoid tissues, and tolerability were evaluated in support of its potential use as a once-monthly antiretroviral agent in humans. Rilpivirine plasma concentration-time profiles showed sustained and dose-proportional release over 2 months in rats and over 6 months in dogs. The absolute bioavailability approached 100%, indicating a complete release from the depot, in spite of rilpivirine concentrations still being high at the injection site(s) 3 months after administration in dogs. For both species, IM administration was associated with higher initial peak plasma concentrations and a more rapid washout than SC administration, which resulted in a stable plasma-concentration profile over at least 6 weeks in dogs. The rilpivirine concentrations in the lymph nodes draining the IM injection site exceeded the plasma concentrations by over 100-fold 1 month after administration, while the concentrations in the lymphoid tissues decreased to 3- to 6-fold the plasma concentrations beyond 3 months. These observations suggest uptake of nanoparticles by macrophages, which generates secondary depots in these lymph nodes. Both SC and IM injections were generally well tolerated and safe, with observations of a transient inflammatory response at the injection site. The findings support clinical investigations of rilpivirine nanosuspension as a long-acting formulation to improve adherence during antiretroviral therapy and for preexposure prophylaxis.

Using experimental design to optimize the process parameters in fluidized bed granulation on a semi-full scale.

A face-centered central composite design was applied in order to optimize the granulation process on a semi-full scale (30-kg batch) for the geometric mean granule size. The granulation process variables investigated were: inlet air temperature, inlet airflow rate, spray rate and inlet air humidity. Based on the process variables, the theoretical powder bed moisture content after the spraying process and a measure for the droplet size were determined. Multiple regression modeling was used to develop two models for the granule size: an empirical model, based on the four process parameters, and a fundamental model, based on the balance between the granule growth affected by the theoretical powder bed moisture content and the droplet size and the breakage effect of the airflow rate. These regression models were used to optimize the granulation process to obtain a granule size between 300 and 500 microm. Additional experiments confirmed that these models were valid. Other granule properties, namely the geometric standard deviation, the Hausner index, the angle of repose and the moisture content, were evaluated at the optimal operation conditions.

Itraconazole Formulation Studies of the Melt-Extrusion Process with Mixture Design

Abstract Itraconazole is a poorly water soluble compound. One method to increase the aqueous solubility of itraconazole is through formation of a solid dispersion. The purpose of this study is to develop a 40% w/w itraconazole formulation through solid dispersion formation, using hydroxypropyl-β-cyclodextrin (HP-β-CD) and hydroxypropylmethylcellulose (HPMC) as mixture components. The solid dispersion was obtained by melt-extrusion using a twin-screw corotating melt extruder. A D-optimal mixture design was applied for the development of the optimal itraconazole formulation. The itraconazole fraction varied between 20% w/w and 50% w/w in the mixture design and the HPMC and HP-β-CD fractions varied between 10% w/w and 60% w/w. The itraconazole formulation was optimized by producing clear extrudates, minimizing the torque, and maximizing the glass transition temperature and the apparent itraconazole solubility in 0.1 N HCl. Regression models were developed for the torque, glass transition temperature, and apparent solubility of itraconazole. High itraconazole fraction in the mixture promoted a better melt processing (minimizes torque). High HPMC fraction (>33% w/w) resulted in clear extrudates, indicating a solid dispersion and resulted in high glass transition temperature of the melt. High HP-β-CD fraction resulted in increased apparent itraconazole solubility in 0.1 N HCl. The optimal itraconazole formulation consisted of 45% w/w HPMC and 15% HP-β-CD w/w.

Study of parameters important in the spheronisation process

Abstract An experimental design was used to determine the influence of parameters that are important in the extrusion-spheronisation process. The parameters tested were water content of binary mixtures of Avicel PH 101 ® /water, spheroniser speed and spheronisation time. They appeared to have a significant influence on the quality of the spheres. By using a Pareto analysis, optimal parameter settings for water content, spheroniser speed and spheronising time were obtained.

Influence of amount of granulation liquid on the drug release rate from pellets made by extrusion spheronisation

Abstract Pellets were prepared by extrusion spheronisation using microcrystalline cellulose as pellet forming agent and two drugs with different solubility, theophylline monohydrate and sulfamethoxazole. Different amounts of water were used for the granulation step prior to extrusion spheronisation. The amount of granulating fluid used had an influence on the drug release from the pellets. A slower release rate was observed with increasing amounts of granulating fluid. These differences in the release profiles were correlated with differences in hardness, density and structure of the pellets.

Using Experimental Design to Optimize the Process Parameters in Fluidized Bed Granulation

In this study many parameters were screened for a small-scale granulation process for their effect on the yield of granules between 75 and 500 μm and the geometrical granule mean size (d50). First a Plackett-Burman design was applied to screen the inlet air temperature, the inlet flow rate, the spray rate, the nozzle air pressure, the nozzle spray diameter, and the nozzle position. The Plackett-Burman design showed that the key process parameters were the inlet flow rate and the spray rate and probably also the inlet air temperature. Afterward a fractional factorial design (25−2) was applied to screen the remaining parameters plus the nozzle aircap position and the spraying time interval. The fractional factorial design showed that the nozzle air pressure was also important. As the target values for the granule yield (between 75 and 500 μm) and the geometric mean granule size (between 300 and 500 μm) were reached during the screening experiments, further optimization was not considered necessary.

Instrumentation of a gravity feed extruder and the influence of the composition of binary and ternary mixtures on the extrusion forces.

Abstract— A gravity feed extruder was adapted to monitor the extrusion forces, the temperature during processing and the rotational speed of the extruding cylinders. The extruder was used to evaluate the influence of particle size of insoluble material and of product solubility on the extrusion forces. Microcrystalline cellulose, dicalcium phosphate dihydrate and different lactoses were used as model compounds. Difference in lactose and microcrystalline cellulose particle size did not influence extrusion forces. The amount of water in the mixtures to be processed and the initial difference in solubility for some of the lactose types investigated influenced the extrusion forces dramatically. Extrusion forces recorded during processing of a mixture previously granulated in a high shear granulator were higher than when processed in a planetary mixture. Loss of water during high shear granulation is probably the main cause of this phenomenon.