Sam Corveleyn

Formulation and production of rapidly disintegrating tablets by lyophilisation using hydrochlorothiazide as a model drug

The influence of different formulation and process parameters on the characteristics of lyophilized oral dosage forms was investigated. Maltodextrins, gelatins, xanthan gum and hydroxyethylcellulose were evaluated as excipients in the formulation of freeze-dried tablets. The resulting tablets were analysed for mechanical strength, porosity, disintegration time and residual moisture. Scanning electron micrographs of the fracture plane of the tablets were taken. Additionally dissolution tests were performed on lyophilized tablets containing hydrochlorothiazide as a model drug. The concentration of the maltodextrins, used as the matrix forming agent, influenced the integrity and strength of the tablets. Increasing the maltodextrin concentrations resulted in stronger tablets. The concentration of the maltodextrins had also an influence on the pore size of the freeze-dried product. There was no influence of the DE value of the maltodextrin on the characteristics of the tablets. The disintegration time of the tablets was also affected by the maltodextrin concentration. The strength of the tablets depended on the xanthan gum concentration and the tablet dimensions. Compared to the formulations using xanthan gum as a binder in the same concentration, the disintegration time of the tablets containing hydroxyethylcellulose (HEC) was much shorter: 55 s for the xanthan gum formulations and 7 s for the HEC formulations. The in vivo disintegration time was significantly higher at 0.5% (w/v) HEC compared to 0.25% (w/v) (P<0.01). The in vivo disintegration time of the tablets containing hydrolysed gelatin Solugel® LB as a binder was below 23 s for the in vivo tests. Unlike the xanthan gum formulations, no gel-like structure was formed upon contact with the saliva. The strength of the tablets was enhanced by using higher maltodextrin concentrations. The incorporation of hydrochlorothiazide in the formulations induced a decrease in strength of the tablets. The percentage of HCT released within 10 min was 64.55±2.87% and 77.84±8.94% for the reference tablets and the lyophilized tablet formulation, respectively. The addition of PEG 6000 (1% w/v) resulted in an increase of drug release as 93.3% was released from the lyophilized tablets within 10 min. However, the incorporation of PEG 6000 in the formulation resulted in a decrease in the strength of the tablets.

Formulation of a lyophilized dry emulsion tablet for the delivery of poorly soluble drugs

The objective was to develop a dry emulsion tablet for the flash delivery of poorly water soluble drugs using a lyophilization technique. The influence of formulation parameters on the characteristics of the lyophilized dry emulsion (LDE) tablets was investigated. Oil-in-water emulsions were made using a medium chain triglyceride as the oil phase and a maltodextrin solution (5–20% w/v) as the water phase. In addition different emulsifier-tablet binder combinations were evaluated. The emulsions were filled into PVC blisters and freeze-dried. The resulting tablets were analyzed for strength, disintegration time, porosity and residual moisture. X-ray diffractions and scanning electron micrographs (SEM) of the fracture plane of the tablets were taken. Dissolution tests were performed on lyophilized tablets containing hydrochlorothiazide (HCT) as a model drug. A significant influence of the maltodextrin type on the tablet disintegration time was seen. Maltodextrin formulations with a high dextrose equivalent (DE) value (DE38) resulted in a faster disintegration time compared to DE12 and DE24 maltodextrin formulations (p<0.05). There was a significant influence of maltodextrin concentration on tablet strength, disintegration time and porosity. Tablet strength increased significantly with increasing maltodextrin concentration (p<0.05). The porosity of the tablets made with DE38 5%, 10% and 20% (w/v) was 92%, 85% and 81%, respectively. SEM pictures showed an increase in pore diameter with a decreasing maltodextrin concentration. No significant influence of Miglyol 812 concentration on tablet strength was observed. A significant influence of methylcellulose concentration, used as emulsifier-tablet binder (Methocel® E15LV), on tablet strength and disintegration time was observed. Dissolution tests on 25 mg HCT containing tablets resulted in a % HCT release of 35.1% and 24.1% for the LDE tablet and conventional tablet, respectively. No significant influence of the oil content in the LDE tablets on the HCT release was observed. It can be concluded that maltodextrins and methylcellulose are useful excipients in the formulation of LDE tablets. The concentration of maltodextrin, the medium chain triglyceride and methylcellulose influenced the tablet characteristics.

Application of the restricted-access precolumn packing material alkyl-diol silica in a column-switching system for the determination of ketoprofen enantiomers in horse plasma.

The group of LiChrospher ADS (alkyl-diol silica) sorbents that make part of a unique family of restricted-access materials, have been developed as special packings for precolumns used in the LC-integrated sample processing of biofluids. The advantage of these sorbents lies in the direct injection of untreated biological fluids, that is without sample clean-up, the elimination of the protein matrix with a quantitative recovery together with an on-column enrichment. The present method is based on previous work applying UV detection at 260 nm for ketoprofen determinations. Plasma samples introduced to the ADS precolumn using a 0.1 M phosphate buffer, pH 7.0. After washing with the buffer the ADS column was backflushed with the mobile phase 0.01 M phosphate buffer-6% (v/v) 2-propanol-5 mM octanoic acid at a pH of 5.5, thus transporting the analytes to the chiral-HSA (human serum albumin) (100x4.0 mm) column where the separation of the ketoprofen enantiomers was achieved with a resolution factor of 1.4. The developed column-switching method was fully applicable to plasma injections.

Maltodextrins as Lyoprotectants in the Lyophilization of a Model Protein, LDH

AbstractPurpose. Maltodextrins, partially hydrolysed starches, were evaluated as potential lyoprotectants and the effect of combinations of maltodextrins and PEG 8000 on the protection of lactate dehydro genase (LDH) was examined. Methods. LDH activity assays were performed immediately before freezing and after reconstitution. The activity recovery was used as the parameter to evaluate the lyoprotectants. Differential Scanning Calorimetry (DSC) was used to measure the glass transition temperature (Tg′) of the solutions. DSC and X ray diffraction were used to characterise the freeze-dried products. Results. Maltodextrins were found to protect LDH againt inactivation during freeze-drying. The lyoprotection obtained by these maltodextrins is dependent on their D.E. value and the concentration used. The maltodextrin formulations performed as good or better than those containing sucrose and maltose, depending on the concentration used. Freeze dried cakes of maltodextrin formulations were amorphous. In the case of low D.E. maltodextrins, lyoprotection was improved by the addition of PEG 8000 as a cryoprotectant. Conclusions. Maltodextrins could be considered as potential lyoprotectants in lyophilization of proteins.

Bioavailability of hydrochlorothiazide : conventional versus freeze-dried tablets

Abstract The objective of the study was to evaluate the pharmacokinetic parameters and relative bioavailability of freeze-dried rapidly disintegrating tablets (formulation A) and lyophilized emulsion tablets (formulation B) containing 25 mg hydrochlorothiazide as a model drug. The tablets were produced by freeze-drying an o/w emulsion containing Miglyol 812, maltodextrin and Methocel A15LV or a suspension containing maltodextrin, PEG6000 and xanthan gum in blisters. Dissolution tests were performed on the tablets using a USP XXII paddle method. A content uniformity test was done on the tablets using an HPLC method. Eight healthy volunteers participated in the bioavailability study. Each volunteer received in a randomized cross-over design, 25 mg HCT on three occasions. Serum samples were analysed on HCT concentration using a validated HPLC method. The C max and T max values were determined from the individual serum concentration–time profiles, while the AUC 0–24h and T 1/2 were calculated using a software package. Both the lyophilized dry emulsion tablet and the conventional tablet showed similar release profiles, while the formulation of a freeze-dried rapidly disintegrating tablet containing 6 mg PEG 6000 resulted in an increase in HCT in vitro release rate. The calculated AUC 0–24h values were significantly different between the three formulations: the freeze-dried rapidly disintegrating tablet containing 6 mg PEG 6000 showed a significantly higher AUC 0–24h in comparison with the other formulations. The C max value of the formulation A was higher compared to the other, although not significantly. The T max values for the freeze-dried formulations were lower compared to the conventional tablet, although not significantly. The serum half life ( T 1/2 ( β )) ranged from 2.1 to 10.5 h for the three formulations. From these results it can be concluded that freeze-dried tablets containing maltodextrin, xanthan gum and PEG 6000 yielded a higher hydrochlorothiazide bioavailability compared to a conventional tablet.

Near-Infrared (NIR) Monitoring of H2O2 Vapor Concentration During Vapor Hydrogen Peroxide (VHP) Sterilisation

AbstractPurpose. There is an increasing use in the pharmaceutical industry of barrier systems such as transfer isolators, sterilisation tunnels and work station isolators. As Vapor Hydrogen Peroxide (VHP) sterilisation of isolators and lyophilizers becomes an important sterilisation method, there is an acute need for a VHP monitoring system to be used for in-process control and validation. In this study, near infrared (NIR) spectrofotometry was evaluated as a potential technique to monitor hydrogen peroxide. Additionally the H2O2 vapor permeability of different packaging materials, commonly used in steam and ethylene oxide sterilisation, was evaluated. Methods. NIR spectrofotometry, using a gas cell connected with optic fibres, was evaluated as a potential technique to monitor hydrogen peroxide vapor and water vapor during VHP sterilisation of an isolator. A NIR spectrum was taken every 30 s during VHP sterilisation of an isolator. The influence of injection rate, air flow rate, working temperature and gas distribution was investigated. The H2O2 vapor permeability of different packaging materials was determined by placing the gas cell in the sterilisation bags and sealing the bags hermetically. The sterilisation bag was then subjected to VHP sterilisation. Results. The NIR spectra taken at steady state sterilization conditions showed 4 absorption peaks: at 1364,1378 and 1400 nm attributed to water and at 1420 nm attributed to H2O2 vapor. By measuring the absorbance level at these wavelengths, the actual concentration of H2O and H2O2 vapor in the isolator was calculated. The water vapor permeation of the sterilisation bags, measured with NIR, appeared to be equal for all materials tested. Whereas Tyvek® was the most permeable material for hydrogen peroxide vapor (82.7% of the reference concentration outside the bag), only 30% was found in bags made of medical paper. Sterilisation bags consisting of laminate films and PVC sealed to medical paper showed intermediate permeability. Conclusions. Near-infrared (NIR) spectroscopy using a gascell with optic fibres is a useful technique to monitor VHP sterilisation cycles. There was a difference in H2O2 vapor permeability of different packaging materials, commonly used in steam and ethylene oxide sterilisation.

Moisture absorption and desorption of different rubber lyophilisation closures.

Abstract Rubber closures form a critical barrier in the protection of freeze-dried products against the uptake of moisture. In this study, the moisture absorption of different rubber lyophilisation closures at different temperatures and relative humidities (RH) was evaluated, using a Karl Fischer titration–oven combination. Also, the moisture absorption during steam sterilisation and the moisture desorption during subsequent drying of the stoppers was investigated. Five chlorobutyl and three bromobutyl rubber stoppers were used in this study. The moisture level from the stoppers stored during 85 days at 95% RH–40°C was in the range 0.85–1.49% for the bromobutyl stoppers and in the range 1.71–1.99% for the chlorobutyl stoppers, depending on the stopper formulation. The same trend in moisture absorption was seen during steam sterilisation, where the moisture uptake of the chlorobutyl rubber closures was higher (0.82–0.9%) compared with the bromobutyl closures (0.41–0.57%). Moisture desorption after steam sterilisation, during drying at 100°C, depended on the treatment of the stopper, e.g., siliconation. Finally the moisture absorption of a freeze-dried formulation was evaluated after venting the lyophilisation chamber with air, dry nitrogen, dry helium or closing the vials under vacuum with two different rubber closures. There was no moisture desorption in the rubber closures during the lyophilisation process. Moisture uptake of the freeze-dried cakes depended on the venting procedure of the lyophilisation chamber after freeze-drying.

Direct HPLC analysis of ketoprofen in horse plasma applying an ADS-restricted access-phase.

Making up part of the unique family of restricted access materials (RAM) the Lichrospher ADS (alkyl-diol silica) sorbents have been developed as special packing materials for precolumns used for LC-integrated sample processing of biofluids. The advantage of such phases consists of direct injection of untreated biological fluids without sample clean-up and elimination of the protein matrix together with an on-column enrichment. The plasma samples, with internal standard phenacetin added (not essential), were brought onto the precolumn (C-18 ADS, 25 micron, 25 x 4 mm i.d.) using a phosphate buffer, 0.1 M, pH 7.0. After washing with the buffer, the ADS column was backflushed with the mobile phase phosphate buffer 0. 05 M pH 7.0: acetonitrile (80:20), thus transporting the analytes onto a reversed-phase column Ecocart 125-3 HPLC cartridge with a LiChrocart 4-4 guard column, both packed with LiChrospher 5 micron 100 RP-18; after separation detection was performed in UV at 260 nm. Essential features of the method include the novel precolumn packing, the absence of sample pretreatment, a quantitave recovery, good precision and accuracy, as well as a considerable reduction of analysis time compared to conventional manual methods applied in bioavailability studies.

Stabilization of fully active chymopapain by lyophilization

Abstract The use of maltodextrins, partially hydrolysed starches, was evaluated for the stabilization of fully activated chymopapain, a cysteine proteinase from the papaya latex. Chymopapain was fully activated with cysteine and Na2EDTA. Enzyme activity was determined before and after the stabilization of chymopapain by lyophilization, in the presence of different amounts of lyoprotectants. During 3 years, the stability of one of the formulations was evaluated. Differential Scanning Calorimetry (DSC) was used to determine the shelf temperature of these products, while X-ray diffraction was used to determine the crystallinity of the products. The water content was determined using Karl-Fisher titration. Maltodextrins were found to protect the fully active chymopapain during the lyophilization process. The protection was dependent on their dextrose equivalent (DE) value and independent on the concentration used (2–5% w/v). The degree of protection was as good as that obtained by sucrose. The activity of chymopapain, stabilized by maltodextrin DE 28, was constant when stored for 3 years at room temperature. Freeze-dried cakes of maltodextrin formulations, containing small amounts of cysteine and Na2EDTA, were amorphous. Maltodextrins can be considered as potential lyoprotectants in the lyophilization of fully active cysteine proteinases.

Evaluation of the Emulsifying Properties of Some Cationic Starches

Different cationic potato, maize, and waxy maize starches were evaluated for their emulsifying properties. Emulsions were prepared using 20% (w/w) arachidic oil and 80% (w/w) water. Emulsions with the cationic starches as emulsifier in a concentration ranging from 1% to 5% (w/w) were prepared and characterized by droplet size and viscosity measurements, and the stability was evaluated visually and by electrical conductance measurements. None of the cationic potato, waxy maize starches, and maize starches with a low degree of substitution (DS) showed adequate emulsifying properties. Emulsions prepared using non-pregelatinized (C [symbol: see text] bond 05914, 2% and 5% w/w; C [symbol: see text] bond 05907, 5% w/w) and pregelatinized (C [symbol: see text] bond 12504, 5% w/w) cationic maize starches with high-DS were visually stable. The initial mean droplet volume diameter of the emulsions prepared with these cationic starches in a 5% (w/w) concentration was similar and ranged from 2.40 to 2.84 microns; however, there was an important difference in droplet size distribution. The droplet size distribution of the emulsions prepared using the non-pregelatinized high-DS cationic starches was markedly narrower than in the case of the emulsions prepared using the pregelatinized high-DS cationic starches. The droplet size of the emulsions remained almost constant during 120 days of storage. Visual inspection and electrical conductance measurements showed that these emulsions were stable for at least 120 days.