Cutting edge technology

Quitterie Lucas, Sandrine Isz and Brigitte Clanachin from Alpha M.O.S. discuss the use of an electronic nose to ensure the quality control of otc tablets

Taste and aroma development and selection of oral dosage formulations are challenging tasks for the formulation department in the pharmaceutical industry.The use of sensory panellists is very difficult due not only to the subjectivity of panel members, but also to the potential toxicity of drugs. Problems in recruiting taste panellists, motivation and panel maintenance are significantly more crucial when working with unpleasant products. Moreover, non-FDA approved molecules cannot be tasted, delaying the moment when the r&d department can obtain the authorisation to taste or smell new medicines or formulations.

At the same time, taste and aroma are competing factors in the pharmaceutical industry for over-the-counter (otc) and prescription drugs, particularly for oral dosage formulations for children or elderly patients. The electronic nose and electronic tongue technologies developed by Alpha M.O.S, of France, offer a fast, objective and simple organoleptic assessment of formulations or oral dispersive tablets. E-nose and E-tongue allow the formulation pharmacists to qualify rapidly, objectively and easily the taste of new formulations in accordance with sensory measurements.

The new instruments analyse, recognise and identify aroma or taste in complex liquid matrices (gel, syrups) or soluble tablets or films.

In the pharmaceutical industry, the E-tongue is used for various applications such as:

• the evaluation and quantification of bitterness of New Chemical Entities or prescription drugs;

• the simplification of selecting the most efficient masking formulations;

• monitoring of aroma and taste stability in accelerated shelf life studies of formulations from both a qualitative and a quantitative point of view;

• monitoring of the quality of taste and aroma through the scale-up process;

• the development of a placebo;

• tablet raw materials quality control for binders, fillers, coatings and residual solvents.

taste 'fingerprint'

The E-tongue, like a human tongue, makes a fingerprint of the taste substances and other dissolved compounds in liquid samples. A liquid sensor array is then used to create a liquid and taste fingerprint of the product, after which a classification process can be carried out by comparing the samples with a database previously built with a set of standard samples. The results can be both quantitative (e.g. concentration, taste scale) and qualitative (identification, conform/non-conform).

The instrument includes a liquid autosampler, an array of individual partially specific liquid sensors that are sensitive to various taste attributes specially designed for the pharmaceutical industry, an electronic unit for sensor measurements and an advanced chemometric software package. The throughput is one sample every three minutes, and although no preparation is required, the sample must be liquid.

The majority of drugs in tablets have a naturally bitter taste, so to make sure patients complete the course of treatment, this bitterness needs to be disguised. Masking the bitterness of the drug has turned into a selling point and become an important parameter in the industry. The E-Tongue quickly evaluates the bitterness masking efficiency of different kinds of formulations.

The method consists of comparing the various formulations with and without the therapeutic drug concentration.

All the analyses are presented on a PCA (Principal Component Analysis) map. Fingerprints of both formulations with different concentrations of masking agents are developed with the aim of testing and tasting objectively a large number of formulations, then reducing the number of formulations to be sensory panel tasted.

To choose the best concentration of the bitterness masking agent, taste difference distances between drug and placebo formulations are determined.

The best bitterness masking formulation is the one giving the shortest distance between the drug and the placebo formulations. The shorter the distance, the smaller the taste difference. Figure 1 corresponds to an antibiotic tablet formulation with increasing concentrations of various sweeteners.

All the placebo formulations are in the same part of the PCA graph (left part in light blue) whereas the drug formulations are located in the right part of the PCA graph (in dark blue). By varying the formulations, the trend of the placebo formulation and drug formulation fingerprints converges to the same point. Dynamic measurements in artificial saliva can also be performed.

Alpha M.O.S, in a collaborative agreement with Ethypharm, has developed a methodology which measures objectively the bitterness intensity of pharmaceutical drugs. Thanks to ongoing research efforts, a first scale in bitterness units is available. This has been built by calibrating the E-Tongue in terms of bitterness intensity using drugs with different bitterness levels.

The E-Tongue predicts the bitterness intensity of a drug that has not been tasted with an average deviation between the tongue prediction and in vivo measurements with trained panellists of 1.9 on a scale of 20 Bitterness Unit. This accuracy is far better than that of the sensory panels (Figure 2).

The control of taste and flavour attributes of drug formulations from the pre-formulation stage to full-scale production is also a major challenge. Monitoring the product consistency can be carried out across multiple sites, regions or even at contract manufacturers using the E-Tongue.

This new technology makes it possible for scientists in charge of product development to monitor the taste quality of drugs formulations.

These tests ensure that the taste of the products fits the expectations of consumers without the difficulties and challenges of human sensory testing. Figure 3 shows results for the scaling up process.

The low requirement of sample preparation using electronic sensing technologies, simplicity, speed of analyses make the E-Tongue very advantageous versus current methods for taste masking.

In research and development as well as quality control fields, the E-Tongue brings objectivity and safety to the pharmaceutical industry when it comes to taste and aroma.