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

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Abstract

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.

Introduction

Most pharmaceutical dosage forms for oral administration are formulated to be swallowed or chewed in order to deliver the drug. Pediatric and geriatric patients may have difficulties swallowing or chewing these tablets. Tablets that rapidly dissolve upon contact with saliva in the buccal cavity could present a solution to those problems and so there is an increased interest in fast dissolving dosage forms for buccal, sublingual and oral administration. Oral lyophilized products combine the properties of freeze-dried dosage forms as fast reconstitution, good preservation and stability, with the benefits of liquid dosage forms for bioavailability (Jaccard and Leyder, 1985).

In this study, 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 possible excipients in the formulation of freeze-dried tablets. Additionally dissolution experiments were performed using hydrochlorothiazide (HCT) as a model drug. HCT was chosen as a poorly soluble drug because the objective was to look at the influence of structure disruption of lyophilised tablets in the presence of `suspended' material.

Section snippets

Materials

The spray dried maltodextrins (Eridania-Beghin Say-Cerestar, Vilvoorde, Belgium) were obtained by enzymatic hydrolysis of corn starch, and had different dextrose equivalents (D.E.): C(PUR01910 (D.E.=14), C(PUR01921 (D.E.=22), C(PUR01934 (D.E.=38). Xanthan gum (Ludeco, Brussels, Belgium) and Idroramnosan® (hydroxyethylcellulose 2% w/v: 5800 mPa.s) (Ludeco, Brussels, Belgium) and different gelatins (PB Gelatins, Vilvoorde, Belgium): hydolysed gelatins Solugel® LB (Bloom value 10–30 g) and

Results and discussion

Rapidly dissolving tablets can be an interesting oral dosage form for geriatric and pediatric patients. The effectiveness of a sublingual piroxicam fast dissolving dosage form based on lyophilisation has been reported (Auvinet et al., 1995). The choice of the binding agent is an important parameter in the formulation of these products. In a formulation study using lactose as a filler, Vennat et al. (1993)reported that the best results in disintegration time of lyophilised tablets were obtained

Acknowledgements

The authors wish to thank Eridania-Béghin Say-Cerestar (Vilvoorde, Belgium) for the generous supply of the maltodextrins and for the use of the texture analyser. The gelatins were kindly provided by PB Gelatins (Vilvoorde, Belgium). Prof. Wettinck (Lab. Non-Ferrometallurgie, University of Gent, Belgium) is kindly acknowledged for the use of the Scanning Electron Microscope.

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