Optimization of tablet formulations

In the optimization of tablet formulations, different approaches can be used. The one variable at a time method requires many experiments and there is no guarantee that an optimal formulation is achieved. Moreover the interaction between different factors, which may influence the tablet properties, will not be detected [10]. The use of an experimental design can be helpful in the optimization of tablet formulations. Mixture designs can be used to describe the response (tablet properties) as a function of the... 

Dawoodbhai S, Suryanarayan ER, Woodruff CW. Optimization of tablet formulations containing talc. Drug Dev Ind Pharm 1991 17 1343-1371. 

Wu et al. [46] used the approach of an artificial neural network and applied it to drug release from osmotic pump tablets based on several coating parameters. Gabrielsson et al. [47] applied several different multivariate methods for both screening and optimization applied to the general topic of tablet formulation they included principal component analysis and... 

This works in the same way as the extended method, except that the only operation is the reflection R. Thus the simplex remains regular (in terms of the coded variables) and the same size, throughout the optimization. Special rules apply when R is worse than W, and for stopping the simplex. See references (13) and (16) for the general rules and reference (17) for a pharmaceutical example, where it is used by Mayne, again to optimize a tablet formulation. 

Colbourn EA, Rowe RC. Modelling and optimization of a tablet formulation using neural networks and genetic algorithms. Pharm Tech Eur 1996 8(9) 46-55. 

This optimization method, which represents the mathematical techniques, is an extension of the classic method and was the first, to our knowledge, to be applied to a pharmaceutical formulation and processing problem. Fonner et al. [15] chose to apply this method to a tablet formulation and to consider two independent variables. The active ingredient, phenylpropanolamine HC1, was kept at a constant level, and the levels of disintegrant (corn starch) and lubricant (stearic acid) were selected as the independent variables, X and Xj. The dependent variables include tablet hardness, friability, volume, in vitro release rate, and urinary excretion rate in human subjects. 

Other applications of the previously described optimization techniques are beginning to appear regularly in the pharmaceutical literature. A literature search in Chemical Abstracts on process optimization in pharmaceuticals yielded 17 articles in the 1990-1993 time-frame. An additional 18 articles were found between 1985 and 1990 for the same narrow subject. This simple literature search indicates a resurgence in the use of optimization techniques in the pharmaceutical industry. In addition, these same techniques have been applied not only to the physical properties of a tablet formulation, but also to the biological properties and the in-vivo performance of the product [30,31]. In addition to the usual tablet properties the authors studied the following pharmacokinetic parameters (a) time of the peak plasma concentration, (b) lag time, (c) absorption rate constant, and (d) elimination rate constant. The graphs in Fig. 15 show that for the drug hydrochlorothiazide, the time of the plasma peak and the absorption rate constant could, indeed, be... 

An MEKC method for the determination of ibuprofen, codeine phosphate hemihydrate, their nine potential degradation products, and impurities in a commercial tablet formulation was developed, optimized, and fully validated according to ICH guidelines and submitted to the regulatory authorities. The optimized system containing ACN as organic modifier allowed baseline separation of ibuprofen, codeine, and nine related substances within 12 min. 

When tablet formulations are made, usually different quality criteria have to be met, e.g., a high crushing strength, a low disintegration time, a pre-set dissolution profile. A tablet consists normally of the pharmacon (the pharmacologically active compound the drug) and excipients. Hence, a tablet can be made with different relative amounts of excipients (a mixture composition) and this creates room for optimizing a tablet... 

For the optimization of, for instance, a tablet formulation, two strategies are available a sequential or a simultaneous approach. The sequential approach consists of a series of measurements where each new measurement is performed after the response of the previous one is knovm. The new experiment is planned according to a direction in the search space that looks promising with respect to the quality criterion which has to be optimized. Such a strategy is also called a hill-climbing method. The Simplex method is a well known example of such a strategy. Textbooks are available that describe the Simplex methods [20]. 

Some key attributes of coated products and coating processes that may well be used to set objectives for optimizing a coating process are shown in Table 2. In many cases, the attributes as listed are very subjective, and thus must be defined in clearly measurable terms if they are to be used as the basis for process optimization. Additionally, meeting defined objectives may equally be dependent on the existence of certain coating and tablet formulation attributes. Nonetheless, while the information listed in Table 2 is not meant to be all-inclusive, it does provide an idea of the types of responses that could be used as a basis for optimizing a coating process. 

Nazzal, S., Nutan, M., Palamakula, A., Shah, R., Zaghloul, A.A., and Khan, M.A. (2002) Optimization of a self-nanoemulsi ed tablet dosage form of Ubiquinone using response surface methodology effect of formulation ingredientslnt. J. Pharm., 240 103-114. 

Compression speed The formulation should be compressed at a wide range of compression speeds to determine the operating range of the compressor. The adequacy of the material s flow into the dies will be determined by examining the tablet weights. Is a force feeder required to ensure that sufficient material is fed into the dies Compression/ejection force The compression profile for the tablet formulation will need to be determined to establish the optimal compression force to obtain the desired tablet hardness. The particle size/size distribution or level of lubricant may need to be adjusted in order to have a robust process on a high-speed compressor. 

H. R. Chueh, H. Zia, and C. T. Rhodes. Optimization of sotalol floating and bioadhesive extended release tablet formulations. Drug Dev. Ind. Pharm. 21 1725-1748, 1995. 

Rotthauser, B., Kraus, G., and Schmidt, P. C. (1998), Optimization of an effervescent tablet formulations containing spray-dried L-leucine and polyethylene glycol 6000 as lubricants using a central composite design, Eur. J. Pharm. Biopharm., 46, 85-94. 

Understanding the degradation chemistry of drug with excipients is essential to select proper excipients in the formulation stages [16, pp 101-151]. Drug-excipient compatibility studies are crucial to decide optimal tablet formulation and to understand the possible mechanism in many cases [10,12,14], Drug instability occurs by three types of reactions hydrolysis, oxidation, and aldehyde-amine addition. Table 11 gives reaction types of chemical and physical instability. 

Nowadays, most experimentation on tablet formulation development is still performed by changing the levels of each variable (factor) at a time, in an unsystematic way, keeping all other variables constant in order to study the effects of that specific variable on the selected response or to find the optimal conditions of a complete system. This methodology (trial and error) is based on a large number of experiments and often relies merely on the analyst s experience [31]. 

Castellanos Gil, E., Iraizoz Colarte, A., Bataille, B., Pedraz, J. L., and Heinamaki, J. (2006), Development and optimization of a novel sustained-release dextran tablet formulation for propranolol hydrochloride, Int. J. Pharm., 317, 32-39. 

Various approaches can be used to solve picking and sticking problems during tablet manufacturing, namely optimization of press tooling, process parameters, and formulation. Generally, it is important to find the optimal combination of formulation and process parameters, particularly when market image tablets are to be produced. 

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