Non Classical Experimental Designs in Pharmaceutical Formulation

Abstract

Classical experimental designs suitable for studying the effect of the proportions of the components on the properties of a mixture are readily developed and are of optimum efficiency. Their applicability depends however on the experimental factor space having a very simple form, and because of the many limits imposed on the levels of pharmaceutical excipients in pharmaceutical dosage forms their practical use in formulation is restricted.

Methods are available for defining the experimental factor space where it is not a simplex and the number of components is too large for the space to be defined graphically. A relatively easy method of obtaining good experimental designs is to use the D-optimum criterion, where a given number of experiments is selected out of the many possible mixtures, to give a statistically optimized design.

An example of the use of this method in formulating a modified release matrix tablet, containing 5 variable components is described. One of the advantages of the method is the possibility of a step-wise approach, and this is demonstated in the present case where the formulation was carried out in two stages. The results enabled the formulation of tablets with the desired dissolution characteristics together with a fairly complete characterisation of the system.     

Non Classical Experimental Designs in Pharmaceutical Formulation

Classical experimental designs suitable for studying the effect of the proportions of the components on the properties of a mixture are readily developed and are of optimum efficiency. Their applicability depends however on the experimental factor space having a very simple form, and because of the many limits imposed on the levels of pharmaceutical excipients in pharmaceutical dosage forms their practical use in formulation is restricted.

Methods are available for defining the experimental factor space where it is not a simplex and the number of components is too large for the space to be defined graphically. A relatively easy method of obtaining good experimental designs is to use the D-optimum criterion, where a given number of experiments is selected out of the many possible mixtures, to give a statistically optimized design.

An example of the use of this method in formulating a modified release matrix tablet, containing 5 variable components is described. One of the advantages of the method is the possibility of a step-wise approach, and this is demonstated in the present case where the formulation was carried out in two stages. The results enabled the formulation of tablets with the desired dissolution characteristics together with a fairly complete characterisation of the system.     

Selection of Active Factors by Stepwise Regression in the Data Analysis of Supersaturated Design

Supersaturated design is a type of fractional factorial design in which the number of columns is greater than the number of rows. Several articles have considered methods for constructing supersaturated designs to assure a low level of nonorthogonality for all paired columns. Stepwise selection is recommended for the selection of active factors in data analysis for supersaturated design, under an assumption of the effect sparsity. This article considers selection errors of stepwise regression in the analysis of supersaturated designs. Specifically, type II error in the selection of stepwise regression is examined using simulation. Based on the results of simulation, some guidelines for data analysis of supersaturated design are discussed.     

Formulation Factors Affecting Thimerosal Stability

Abstract

A high-performance liquid chromatographic (HPLC) assay has been developed for thimerosal and some of its degradation products: thiosalicylic and 2,2′-dithiosalicylic acids. Using this method, the influence of formulation factors as: isotonic agent, initial concentration, addition of tromethamine, pH and container material, over thimerosal stability was studied.     

Formulation Factors Affecting Thimerosal Stability

A high-performance liquid chromatographic (HPLC) assay has been developed for thimerosal and some of its degradation products: thiosalicylic and 2,2'-dithiosalicylic acids. Using this method, the influence of formulation factors as: isotonic agent, initial concentration, addition of tromethamine, pH and container material, over thimerosal stability was studied.     

Relative Efficiency of R2 and B2 in Regression Analysis for Calibration and Formulation

Abstract

The assessment of the adequacy of a regression equation, as measured by the degree of closeness of the predicted values and their respective observed values is accomplished by the two contending statistics, R² and B². The derivation of the two statistics is presented and their relative performances are examined in the context of several pharmaceutics experiments involving, calibration, validation and formulation. The results strongly indicate that the B²-statistic is much more sensitive and efficient than the R²-statistic which has a tendency to inflate the magnitude irrespective of the data structure.     

Relative Efficiency of R2 and B2 in Regression Analysis for Calibration and Formulation

The assessment of the adequacy of a regression equation, as measured by the degree of closeness of the predicted values and their respective observed values is accomplished by the two contending statistics, R² and B². The derivation of the two statistics is presented and their relative performances are examined in the context of several pharmaceutics experiments involving, calibration, validation and formulation. The results strongly indicate that the B²-statistic is much more sensitive and efficient than the R²-statistic which has a tendency to inflate the magnitude irrespective of the data structure.     

业务流程重组成功因素分析

企业业务流程重组是企业绩效获得巨大改善的必要条件,然而大多数重组实践是以失败而告终的。文章从分析业务流程重组的内涵入手,研究ＢＰＲ失败的原因,并在此基础上提出了与ＩＥ技术相结合、必须直接领导重组等引导ＢＰＲ走向成功的关键因素。     

Analysis of Survival Data by Regression Techniques

The nature of the process of retirement of groups of industrial properties is so complex that it is difficult to postulate adequate mathematical models such aa those, employed in life-testing, etc. Assuming that there exists a survivor function, M(t), representing the proportion of a group remaining in service at time t, such function is given by exp [–y(t)], where y(t) is the time integral of the retirement rate, r(t) = –d(logM(t))/dt. Rather than to hazard a guess aa to the parametric form of any of these functions, it is the intent of this paper to approximate the integral, y(t), by a polynomial, whereupon M(t) may be graduated by the descending exponential function. For large samples it is found that the covariance structure for the polynomial regression of y(t) on t may be obtained from the multinomial distribution when the data are grouped. Thus the method of weighted least squares may be employed in fitting y(t). “Censored” data in no way vitiate the method.     

增材制造用金属粉末材料的关键影响因素分析

通过分析增材制造过程中各因素的影响作用,提出材料是制约我国增材制造技术的主要问题,对增材制造用粉末材料的特点进行了解析,以期为解决我国增材制造用粉末的研发提供参考。     

Ordinal Logistic Regression Model of Failure Mode and Effects Analysis (FMEA) in Pharmaceutical Tabletting Tools

The main objective of this paper is to use Ordinal Logistic Regression Modeling (OLRM) to predict and to investigate the relationship(s) between the different types of failures encountered in tableting tools of pharmaceutical industry and relevant tablet- and punch attributes. This would help minimize the occurrence of such failures in and avoid potential failure occurrences in future punch designs. Three punch attributes (punch diameter, location and shape) and five product attributes (tablet mass (gm), hardness (Kp), thickness (mm), moisture content (percent loss on drying (LOD %)) and sieve size (mm)) have been investigated in terms of their relative contributions towards different failure types. The present OLRM model has been successfully applied to the predict failure types according to the aforementioned factors. Furthermore, OLRM quantitatively links and evaluates the effects and contribution of each of these factors to the occurrence of different failure types. The OLRM methodology has been validated conveniently and proved to be powerful prediction tool. This is indicated by the marginal 2.4% error percentage encountered.     

回归分析法简化钻爆设计

以某工程钻爆参数为例,阐述了在地下工程掘进施工中,应用回归分析法建立钻爆参数的相关模型,并利用此模型帮助建立某断面钻爆方案.     

影响喷墨印刷质量的关键因素分析

介绍喷墨印刷成像原理,以热喷墨成像系统为研究对象,探讨该系统成像机理、油墨和受像介质之间的相互关系以及对喷墨印刷质量的影响,并对如何控制关键参数进行了讨论.     

Application of Neural Computing in Pharmaceutical Product Development: Computer Aided Formulation Design

Abstract

Most pharmaceutical products are complex systems designed to meet several compendial or other performance standards simultaneously. Ideal or ‘optimum’ product composition and the manufacturing process variables are generally established after extensive experimentation. Artificial Neural Networks are pattern recognition tools that allow the development of ‘expert’ systems without having to write computer programs. With this technology it may be possible to develop formulation ‘expert’ systems to predict the formulation composition and the manufacturing process conditions necessary to achieve the desired performance standards. This report introduces the concept of a formulation expert system to predict the in vitro drug release profile from hydrophilic matrix tablets. Formulation expert systems or Computer Aided Formulation Design has the potential to reduce the time and cost of the product development process.     

Application of Neural Computing in Pharmaceutical Product Development: Computer Aided Formulation Design

Most pharmaceutical products are complex systems designed to meet several compendial or other performance standards simultaneously. Ideal or 'optimum' product composition and the manufacturing process variables are generally established after extensive experimentation. Artificial Neural Networks are pattern recognition tools that allow the development of 'expert' systems without having to write computer programs. With this technology it may be possible to develop formulation 'expert' systems to predict the formulation composition and the manufacturing process conditions necessary to achieve the desired performance standards. This report introduces the concept of a formulation expert system to predict the in vitro drug release profile from hydrophilic matrix tablets. Formulation expert systems or Computer Aided Formulation Design has the potential to reduce the time and cost of the product development process.