Studies on development of insoluble drugs as pharmaceutical suspensions by response surface methodology.

The preformulation of insoluble drugs, trimethoprim and nitrofurantoin, was studied in order to achieve a suspension with desirable requirements. The objective of the formulator is to avoid the irreversible aggregation called "caking", and to obtain a suspension with an airy, large volume sediment easily redispersible and with suitable rheological properties. An experimental design useful to determine optimal properties is a Box-Behnken design. The surfactant, thickener and electrolyte at different proportions were the three factors studied. This strategy allows to point on the main significant effect and to determine the concentrations of each product leading to optimal properties of the suspensions.

Using factorial design to improve the solubility and in-vitro dissolution of nimesulide hydrophilic polymer binary systems.

The aim of the present study was to use factorial design to enhance the dissolution rate of nimesulide using solid binary systems with the hydrophilic carriers D-mannitol and polyethylene glycol (PEG 4000). Two-factor full factorial design was employed to investigate the effects of the drug/carrier ratio (X(1), 10 and 20%) and the method of　preparation (X(2), physical or co-melted mixture) on　the percent drug release after 60 min (Y(1)). Drugcarrier co-melted mixtures were prepared by melting the carriers D-mannitol or PEG with the drug. For physical mixtures, the drug and carrier were mixed thoroughly in a mortar until a homogeneous mixture was obtained. Drug-carrier interactions were investigated by differential scanning calorimetry (DSC). All prepared mixtures were filled in hard gelatin capsules, size 0, and then their dissolution rate was tested. The results showed an increase in the solubility of the drug with increasing polymer concentrations. Thermal analysis revealed no notable differences regarding thermal events of nimesulide, D-mannitol, PEG 4000, and their physical or comelted mixtures. The percent drug released after 60 min was 29.5% for nimesulide alone, 37.14 and 32.0% for a PEG/Physical mixture with a 10 or 20% drug/polymer ratio, and 69.7 and 53.1% for a PEG/Co-melted mixture with the same ratios. For nimesulide/D-mannitol, this percent drug released was 33.57 and 29.6% for a physical mixture and 63.13 and 48.04% for a co-melted mixture. Formulations with PEG showed an increase in solubility as well as dissolution in comparison to those prepared with D-mannitol. Factorial design was successfully used to optimize the dissolution rate of nimesulide. The chosen polymers caused a notable increase in drug solubility and co-melted formulations generally showed a higher dissolution than those prepared with physical mixtures.

Studies on the development of rapidly disintegrating hyoscine butylbromide tablets.

The objective of this study was to prepare hyoscine butylbromide (a drug with bitter taste) tablets that can rapidly disintegrate in saliva. The granules were prepared by the extrusion method using aminoalkyl methacrylate copolymers (Eudragit E-100). The drugs dissolved rapidly in medium at pH 1.2 in a dissolution test while none of the drugs dissolved from the granules (% of dissolved < 5%) even after 8 h at pH 6.8. Rapidly disintegrating tablets were prepared using prepared taste-masked granules and a mixture of excipients consisting of crystalline cellulose (Avicel PH-102) and low substituted hydroxypropylcellulose (L-HPC, LH-11).The granules and excipients were mixed well (mixingratio by weight, crystalline cellulose: L-HPC, was 8:2) with 1% magnesium stearate as a lubricant and subsequently compressed at 500-1,500 kgf in a single-punch tableting machine. The prepared tablets (compressed at 500 kgf) containing the taste-masked granules have significant strength (crushing strength was 3.5 kg), and a rapid disintegration time (within 30 sec) was observed in the saliva of healthy volunteers. None of the volunteers sensed any bitter taste after the disintegration of the tablet that contained the taste-masked granules. The results confirmed that rapidly disintegrating tablets can be prepared using these taste-masked granules and excipients that are commonly used in tablet preparation.