Multivariate Methods in the Development of a New Tablet Formulation: Excipient Mixtures and Principal Properties

ABSTRACT

A tablet formulation for direct compression has previously been studied using multivariate design. An optimization study of one of the most important tablet properties, disintegration time, revealed that excipients with Principal Properties (PP's) that were predicted as suitable by the model were not represented within the studied material.

The feasibility of using mixtures of excipients in the multivariate approach to tablet formulation to solve this problem has been investigated in the present study. By mixing different excipients of the same excipient class, it should be possible to obtain mixtures with the predicted PP's, which in turn should give a formulation with the desired properties. In order to investigate the utility of this approach, separate mixture designs were applied to both binders and fillers (diluents).

As reported here, the Partial Least Squares Projections to Latent Structures (PLS) model developed in the previously published screening study has been validated in the sense that the interesting region of the PP space identified in it has been shown to contain excipients, pure or mixed, that give the formulation suitable properties. Formulations with suitable properties were found with the mixture experiments. The local models also offer several alternatives for the composition of the formulation that yield the desired disintegration time.     

Multivariate Methods in the Development of a New Tablet Formulation: Optimization and Validation

In a previous study of the development of a tablet formulation approximately 100 excipients were characterized in screening experiments using multivariate design. Acceptable values for important responses were obtained with some of the formulations. The relationships between the properties of the excipients and the responses were evaluated using PLS. In this study additional experiments were performed in order to validate models obtained from the screening study and to find a formulation of suitable composition with desired tablet properties. A formulation with the desired disintegration time was found with the additional experiments and the agreement between observed and predicted values was fair for the tablets that did disintegrate. A limitation of this study was that tablets from four experiments did not disintegrate within the set time limit. The lack of agreement between observed and predicted values of these four experiments was probably due to the nature of one of the factors in the design. Considering the reduced experimental design the results are still encouraging.     

Robustness Testing of a Tablet Formulation Using Multivariate Design

ABSTRACT

A total of 45 experiments were carried out to evaluate the robustness of two similar tablet formulations—a product of two strengths—with respect to normal batch-to-batch variation of the excipients and the active pharmaceutical ingredient. The formulations consist of 10 ingredients. Because of the differing amounts of active pharmaceutical ingredients, the two formulations also differ in the amounts of two of the diluents and one of the binders. The excipients and active pharmaceutical ingredient were characterized in terms of multiple variables, and principal properties were calculated with principal component analysis. A Plackett and Burman design was applied to the principal properties. The relationships between the design factors and two responses, mean disintegration time and mean crushing strength, were evaluated by using regression methods. Both formulations were found to be robust under controlled conditions.     

Multivariate methods in the development of a new tablet formulation: optimization and validation

In a previous study of the development of a tablet formulation approximately 100 excipients were characterized in screening experiments using multivariate design. Acceptable values for important responses were obtained with some of the formulations. The relationships between the properties of the excipients and the responses were evaluated using PLS. In this study additional experiments were performed in order to validate models obtained from the screening study and to find a formulation of suitable composition with desired tablet properties. A formulation with the desired disintegration time was found with the additional experiments and the agreement between observed and predicted values was fair for the tablets that did disintegrate. A limitation of this study was that tablets from four experiments did not disintegrate within the set time limit. The lack of agreement between observed and predicted values of these four experiments was probably due to the nature of one of the factors in the design. Considering the reduced experimental design the results are still encouraging.     

Multivariate Methods in Developing an Evolutionary Strategy for Tablet Formulation

The aim of this study was to develop a new strategy for choosing excipients in tablet formulation. Multivariate techniques such as principal component analysis (PCA) and experimental design were combined in a multivariate design for screening experiments. Of a total 87 investigated excipients, the initial screening experiments contained 5 lubricants, 9 binders, and 5 disintegrants, and 35 experiments were carried out. Considering a reduced factorial design was used, the resulting PCA and partial least squares (PLS) models offered good insight into the possibilities of tablet formulation. It also offered solutions to the problems and clearly gave directions for optimum formulations. Further, it offered several alternatives for achieving quality formulations. Additional experiments conducted to validate and verify the usefulness of the model were successful, resulting in several tablets of good quality. The conclusion is that a multivariate strategy in tablet formulation is efficient and can be used to reduce the number of experiments drastically. Combining multivariate characterization, physicochemical properties, experimental design, multivariate design, and PLS would lead to an evolutionary strategy for tablet formulation. Since it includes a learning strategy that continuously incorporates data for new compounds and from conducted experiments, this would be an even more powerful tool than expert systems.     

Two Projection Methods for Use in the Analysis of Multivariate Process Data With an Illustration in Petrochemical Production

Principal components analysis (PCA) is often used in the analysis of multivariate process data to identify important combinations of the original variables on which to focus for more detailed study. However, PCA and other related projection techniques from the standard multivariate repertoire are not explicitly designed to address or to exploit the strong autocorrelation and temporal cross-correlation structures that are often present in multivariate process data. Here we propose two alternative projection techniques that do focus on the temporal structure in such data and that therefore produce components that may have some analytical advantages over those resulting from more conventional multivariate methods. As in PCA, both of our suggested methods linearly transform the original p-variate time series into uncorrelated components; however, unlike PCA, they concentrate on deriving components with particular temporal correlation properties, rather than those with maximal variance. The first technique finds components that exhibit distinctly different autocorrelation structures via modification of a signal-noise decomposition method used in image analysis. The second method draws on ideas from common PCA to produce components that are not only uncorrelated as in PCA, but that also have approximately zero temporally lagged cross-correlations for all time lags. We present the technical details for these two methods, assess their performance through simulation studies, and illustrate their use on multivariate output measures from a fluidized catalytic cracking unit used in petrochemical production, contrasting the results obtained with those from standard PCA.     

Development of a New Tablet Formulation of Theophylline: In Vitro and in Vivo Studies

The preparation of a new scored 250 mg theophylline tablet is described, for which effects of particle size of the active principle, aspects of granulation and changes in tabletting settings were investigated.

In vitro studies showed the dissolution rate from tablets prepared from theophylline of commercial quality (50 μm) or of selected particle size (30 μm) to be faster than that from tablets prepared from micronized theophylline (10 μm). In vivo studies in dog showed that only the tablet from theophylline of selected particle size has the same bioavailability as an aqueous solution.

The scale up study showed that the characteristics of the tablets, including dissolution rate, are independent of the formulation factors.     

Robustness testing of a tablet formulation using multivariate design

A total of 45 experiments were carried out to evaluate the robustness of two similar tablet formulations—a product of two strengths—with respect to normal batch-to-batch variation of the excipients and the active pharmaceutical ingredient. The formulations consist of 10 ingredients. Because of the differing amounts of active pharmaceutical ingredients, the two formulations also differ in the amounts of two of the diluents and one of the binders. The excipients and active pharmaceutical ingredient were characterized in terms of multiple variables, and principal properties were calculated with principal component analysis. A Plackett and Burman design was applied to the principal properties. The relationships between the design factors and two responses, mean disintegration time and mean crushing strength, were evaluated by using regression methods. Both formulations were found to be robust under controlled conditions.     

Multivariate calibration of non-replicated measurements for the factored noise model

The accuracy of a multivariate calibration (MVC) model for relating concentrations of multicomponent mixtures to their spectral measurements depends on effective handling of errors in the measured data. For the case when error variances vary along only one mode (either along mixtures or along wavelengths), a method to estimate the error variances simultaneously along with the spectral subspace was developed by Narasimhan and Shah (Control Engineering Practice, 16, (2008), 146–155). This method was exploited by Bhatt et al. (Chemom. Intell. Lab. Syst., 85, (2007), 70–81) to develop an iterative principal component regression (IPCR) MVC model, which was shown to be more accurate than models developed using PCR. In this work, the IPCR method is extended to deal with measurement errors whose variances vary along both modes, by using a factored noise model. As a first step, an iterative procedure is developed to estimate the error variance factors along with the spectral subspace, which is subsequently used in developing the regression model. Using simulated and experimental data, it is shown that the quality of the MVC model developed using the proposed method is better than that obtained using PCR, and is as good as the model obtained using Maximum Likelihood PCR, which requires knowledge of the error variances. For dealing with large data sets, a sub-optimal approach is also proposed for estimating the large number of error variances.     

Development of a Raman method to follow the evolution of coating thickness of pellets

Context: Although several methods have been investigated to measure the film thickness of tablets and its correlation with the dissolution behavior, much fewer such investigations exist for pharmaceutical pellets.

Objective: To study the possibility of measuring the film thickness and predicting the dissolution behavior of pellets produced in different fluid bed equipments with Raman spectroscopy.

Materials and methods: Pyridoxine hydrochloride-layered pellets were produced and coated in two different Strea-1 equipments. Raman spectra were collected and analysed to set up a calibration model based on the film thickness data calculated from Camsizer analysis results. Dissolution tests were done according to Ph. Eur. standards.

Results: Raman spectroscopy proved to be a good tool in the measurement of film thickness. Polymer weight gain showed a linear correlation with film thickness but was a poor predictor of dissolution results below a threshold value.

Conclusion: The Raman spectroscopic measurement of a small sample can provide accurate data of the film thickness. The investigation suggests that a threshold value might exist for the film thickness above which it can be used to judge future dissolution results.     

Study of Skin Phantoms by Photothermal Radiometry in Frequency Domain and Multivariate Methods

In this paper the use of the photothermal radiometry technique in the frequency domain (PRTF) and the use of multivariate methods in the study of two types of skin phantoms: (a) one in which skin pigmentation was simulated dyeing the gel phantom and (b) the other consists of exposure of animal skin samples to different degrees of thermal damage. In experiment (a), gel phantoms were prepared with different concentrations of methylene blue (MB). The mean values of the radiometry signal (RS) show significant differences in only those cases in which changes in the concentration of MB were higher than 0.38 mM. This result was confirmed with a t test for independent samples of the data (p < 0.05). The mean values of the amplitude and phase signal do not permit discrimination between phantoms with changes in pigmentation equal to or lower than this value. However, principal component analysis (PCA) demonstrated that it is possible to discriminate between phantoms with changes in molar concentration equal to 0.38 mM (for the phase signal). In the case of experiment (b), the following four groups of pork skin samples were analyzed: one consists of samples of fresh skin, while the other three consist of samples exposed to thermal damage at 45 °C (the exposure time was 4 s) and 80 °C (exposure times were 4 s and 8 s, respectively). The mean values of the RS for each group of samples did not show a clear visual discrimination. However, the t test for independent samples applied to the data demonstrated significant differences only between fresh skin and skin exposure to thermal damage at 80 °C (with exposure times of 4 s and 8 s). PCA was used to discriminate between the four different skin samples.     

气溶胶灭火剂的配方及优化设计的研究

文章为了研究气溶胶灭火剂在工程应用中的灭火能力及所遇到的腐蚀问题,采用对比实验方法对K型和S型的气溶胶灭火剂的配方进行了研究。主要选择了以锶盐为主、钾盐为辅的氧化剂,设计并优化了几种配方。结果表明:从灭火效能、喷射时间、Cu板颜色变化等性能参数可以看出,当Sr(NO3)2与KNO3的比值在1.4～5.0范围内效果最好,灭火效能为95 g/m3,喷射时间为42 s,且Cu板没有明显地变绿,既保证了气溶胶的灭火能力,又较好地解决了腐蚀性的问题。     

Mixed Formulation Solution and Optical Based Experimental Methods in the Deformation Analysis of Radially Loaded Cylindrical Shells

Abstract: A mixed formulation in the characterization of internal forces and displacements in cylindrical shells, subjected to radial forces is presented. This numerical approach is proposed as an alternative to the irreducible formulation, where in some problems this solution leads to stress distribution presenting some discontinuity along the edge joining shell modules with different geometry as, for example, curved pipes with tangent terminations. The mixed formulation here proposed prescribes the continuity in the stress field at shell adjacent sections, while practically ensures similar accuracy in the displacement and stress fields. The force and displacement formulations are carried out by combining unknown analytic functions with trigonometric expansions. The solution can be applied to recurrent problems in piping design as is the case of edge forces and radial loads. Examples considering these external parameters are developed and results are compared with an experimental method based on optical interferometric techniques. These procedures were applied with video recording of the interferometric pattern and allow the displacement field assessment with a non‐contact procedure.     

一种可用于灭火的炸药配方设计及应用研究

爆炸法灭火是一种高效、快捷且具有独特应用背景的新型灭火方式.为了简化现有爆炸灭火装置主体结构,提出了一种可用于灭火的炸药构思,通过在现有煤矿许用炸药配方中外加典型添加剂成分,探讨了灭火炸药配方设计原理和方法,给出了灭火药包结构形式,并简要介绍了其在矿井瓦斯爆炸抑爆系统中的应用.文中讨论与分析了优化现有灭火技术、设计较为合理的爆炸灭火药包结构的思路和方法.     

Development of a Lyophilized Formulation for (R,R)-Formoterol (L)-Tartrate

(R,R)-formoterol is a β-agonist for inhalation. Aqueous instability suggested the need for a reconstitutable lyophilized dosage form. The objective of these studies was to devise a stable, rapid-dissolving, therapeutically compatible dosage form. The effects of diluents and residual moisture on the stability of thermally stressed formoterol formulations were investigated. Drug and various excipients (acetate, lactose, and mannitol) were lyophilized and placed in humidity chambers (0 to 90% relative humidity) at 25 to 50°C. Stability was characterized by time-dependent changes using HPLC, pH, and XRD. Residual moistures were determined by Karl Fisher methods. Regression models were developed to quantify the effects of formulation and environmental variation on drug stability. Solid-state instability was observed as a function of high residual moisture and diluent type. Although the residual moistures in mannitol formulations were typically below 1%, the degradation rate (50°C) varied from 2 to 10 mcg/day, which was 1.3- to 20-fold high than observed for lactose formulations under the same relative humidity conditions. At high relative humidity, the presence of acetate significantly increased the degradation rate (p < 0.04). The critical residual moisture content for lactose formulations was 3%. The amount of lactose was optimized by evaluating the degradation over the temperature range 25 to 50°C. Mannitol and acetate were shown to be unsuitable excipients, and an optimal lactose amount was 50 mg for vials containing 50 mcg of drug.     

Formulation of a Fast-Dissolving Ketoprofen Tablet Using Freeze-Drying in Blisters Technique

ABSTRACT

The aim of this work was to develop a ketoprofen tablet which dissolve-rapidly in the mouth, therefore, needing not be swallowed. The solubility and dissolution rate of poorly water-soluble ketoprofen was improved by preparing a lyophilized tablet (LT) of ketoprofen using freeze-drying technique. The LT was prepared by dispersing the drug in an aqueous solution of highly water-soluble carrier materials consisting of gelatin, glycine, and sorbitol. The mixture was dosed into the pockets of blister packs and then was subjected to freezing and lyophilization. The saturation solubility and dissolution characteristics of ketoprofen from the LT were investigated and compared to the plain drug and the physical mixture (PM). Results obtained showed that the increase in solubility of ketoprofen from LT matrix, nearly three times greater than the solubility of the plain drug, was due to supersaturation generated by amorphous form of the drug. Results obtained from dissolution studies showed that LT of ketoprofen significantly improved the dissolution rate of the drug compared with the PM and the plain drug. More than 95% of ketoprofen in LT dissolved within 5 min compared to only 45% of ketoprofen plain drug dissolved during 60 min. Initial dissolution rate of ketoprofen in LT was almost tenfold higher than that of ketoprofen powder alone. Crystalline state evaluation of ketoprofen in LT was conducted through differential scanning calorimetry (DCS) and x-ray powder diffraction (XRPD) to denote eventual transformation to amorphous state during the process. Scanning electron microscopic (SEM) analysis was performed and results suggest reduction in ketoprofen particle size.     

纳米粒子在口服胰岛素制剂中的应用研究

由于胰岛素作为一种蛋白质药物,易被胃肠道中的消化酶降解,降低胰岛素的生物利用度。近年来各种口服胰岛素制剂被开发研究,其中纳米粒子在改善口服胰岛素生物利用度,提高降血糖作用方面具有一定的优势。文中将纳米粒子分为合成高分子材料纳米粒子、天然高分子材料纳米粒子和其他类型纳米粒子,分别从各类纳米粒子特点、生物相容性、体内降血糖效果以及生物利用度等体内体外性能研究方面,对其在口服胰岛素制剂中的应用进行简述。     

论探寻平板电脑设计机会的方法

从目前市场上平板电脑存在的定位模糊问题出发,指出在设计之初对特定人群开展针对其生活形态及行为等分析研究的必要性,并基于群体文化学理论,探讨其在模糊前期对寻找产品机会缺口的意义,提出了运用群体文化学原理在平板电脑开发设计前期的具体应用程序与方法,为相关新产品机会缺口的寻找及产品定位,提供了可操作的方法和步骤。     

Chemometric characterization of s-triazine derivatives in relation to structural parameters and biological activity

Objective: In this study 14 newly synthesized s-triazine derivatives were investigated by means of reversed-phase thin-layer chromatography (TLC) on C-18 stationary and five different mobile phases: acetone–water, acetonitrile–water, methanol–water, 2-propanol–water, and tetrahydrofuran–water. Methods: Principal component analysis (PCA) was performed to explore and visualize similarities and differences among the compounds and among the mobile phases. Observations from the PCA were supported using hierarchical cluster analysis (HCA). Results: Physicochemical parameters that are significant for activity, that is, absorption, distribution, and bonding for different receptors in target tissues were calculated. Conclusion: Highly predictive models, describing quantitative relationships between chromatographic retention and parameters that influence activity, were obtained using partial least squares (PLS) method.