Taste-masked pharmaceutica l compounds
Optimazation by hybridization techniques

Since organoleptic properties have a great impact on patient compliance, marketing and sale of pharmaceutical products various approaches have been made to mask the unpleasant taste and smell of drugs for human or veterinary use. Mainly these approaches include barrier- (coating, encapsulation) and complexation-methods (ion-exchange resins, cyclodextrins).

The major drawbacks of thus formulated drugs are the resulting high particle size, their damage during further processing, their permeability at the pH of the saliva and the complicated technologies involved. These problems could be solved in a very easy, fast and effective way using a technology not very common in the pharmaceutical industry so far: the Nara Hybridization System (NHS). This system is usually used for powder surface-modification and dry powder coating.
Materials and methods
Activated charcoal of pharmaceutical grade and potato starch, respectively, were used as host particles and each mixed with the sparingly soluble, extremely bitter-tasting drug praziquantel as guest particle. The particle size of charcoal was 1–50 µm (see figure 1), of starch <50 µm (see figure 2) and 1–50 µm of the drug (see figure 3). A 20% (w/w) mixture of drug in the excipient was gently mixed and about
100 g of the mixture was placed into the “Hybridization System Type 1” and processed for three minutes at 6000 rpm. In short, such a Hybridizer consists of a very high-speed rotating rotor (5000–16000 rpm) with six blades, a stator and a powder re-circulation circuit. After introduction into the powder inlet the powder mixture is carried on an air stream generated by the blades and circulates in the machine. Strong forces are applied to the material when the particles collide with other particles, the blades, and the inner surface of the machine. If necessary the inner surface of the hybridization chamber can be cooled to decrease the temperature. The yield of the resultant powder was controlled and it was analysed for surface appearance (microscope model Hitachi 2150S), content of the active ingredient (HPLC) and dissolution of the active ingredient (medium 0.1 N HCl, 2% sodium lauryl sulphate). Further the taste of the hybrid powder was checked by organoleptic testing.
Results Yield
The amount of product recovered was 75% for the coating of potato starch with praziquantel. For charcoal a recovery of
90 to 95% was achieved in the coating trials.
Appearance
The hybrid powders differ from another in appearance. The surface of the praziquantel/starch mixture (figure 4) is very smooth and round, no crystal needles from the drug are observed any longer and nearly no crushed praziquantel particles remain as free particles in the mixture. By the physical forces applied the drug seems to be incorporated into the starch particle to a large amount. The particle size of the powder now is similar to that of the raw starch, that is below 50 µm. In contrast to the above the scanning electroscope picture from the praziquantel/charcoal mixture (figure 5) reveals that shape and size of the host particles did not change significantly while the crushed particles of about 1 µm, seen in the raw charcoal before testing, disappeared. No crystal needles of the drug are observed any more. This indicates that the charcoal has absorbed the guest particles.
Content
Analysing the content of praziquantel in both hybrid powders with respect to drug content showed that it did not decrease due to processing compared to the weight ratio of the material at the start. It remained at 20%.
Dissolution
As could be expected due to the physico-chemical properties of the host compounds and to the appearance of the hybrid powders there is a difference in the dissolution of the active ingredient. Figure 6 shows that the release of praziquantel is very fast after hybridizing it with potato starch. After two minutes already 78% are released and about 100% after 20 minutes. In contrast and as can be deduced from Figure 7 the release of praziquantel from charcoal is biphasic with an initial rapid release reaching 53% after ten minutes followed by a sustained release over more than 80 minutes.
Taste
There is also a difference in the quality of the hybrid powders to suppress bitterness. Although, as shown above, the initial dissolution of both mixtures is rather fast there is tremendous difference in taste. While the starch mixture immediately after ingestion has a very bad taste, it is completely neutral when sucking the charcoal mixture.

Discussion
Praziquantel inclusion was achieved by the hybridization method. However it became obvious that the host particle has a great impact on taste and release kinetics of the powder mixtures. In contrast to what was hoped for due to the shape of the particles, the release of praziquantel from the starch mixture was accelerated compared to its intrinsic, original dissolution properties (figure 8). Although it is interesting for
other applications this finding was not investigated further because of the bad taste of the powder mixture. It might be that hybridization overcomes intermolecular forces
leading to an amorphous state of the drug. Or the wet ability of the drug is improved due to the hydrophilic properties of the starch and/or decrease of particle size causing an increase in their surface area. The use of charcoal as an excipient is not common up to now. In general there is a certain equilibrium and also desorption from the charcoal takes place. Rarely advantage has been taken of this fact; up to now desorption has been used specifically only for sustaining the release of drugs (e.g. Roivas, L. “A biopharmaceutical study on activated charcoal as a possible matrix for controlled release”, dissertation Turku 1994). In the present investigations it was found that charcoal is useful for taste masking of lipophilic drugs such as praziquantel. The desorption process of the drug from the charcoal mixture is biphasic (figure 7) with an initial rapid release and development of an equilibrium thereafter. Despite the fast release of the bitter-tasting drug in the dissolution apparatus (53% after ten minutes) surprisingly the taste of the powder mixture was completely neutral and remained perfect during sucking the powder. After 90 minutes in the dissolution apparatus (figure 7) the intrinsic dissolution of praziquantel begins to decrease indicating a stability problem of the drug. This problem is intensified in-vivo since praziquantel shows a distinct first-pass-effect in the liver and is decomposed rather fast to an ineffective metabolite. Such drugs are recommended to be applied in sustained release formulations.
Conclusion
At present wet processes are mainly used to manufacture taste-masked dosage forms or those for sustained release. The data obtained using dry impact blending of praziquantel however suggests that this method could be a more advantageous alternative.