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.     

Evaluation of sorghum starch as a tablet excipient

The suitability of sorghum starch as a binder and disintegrant at various concentrations in diverse tablet formulations have been investigated. Sodium bicarbonate and calcium carbonate were used as soluble and insoluble inorganic medicinal substances in various tablet formulations.

The effect of sorghum starch on the physical properties of the tablets were compared with those formulated with maize starch using the same concentrations of binder and disintegrant under the same experimental conditions.

The observations show that sorghum starch can be used as binder and disintegrant in tablet formulations. The indication is that the starch exhibit about twice the disintegrant power and about the same binding efficacy compared to maize starch.     

Preparation and physicochemical evaluation of a new tacrolimus tablet formulation for sublingual administration

The aim of this study was to develop a new fast-disintegrating tablet formulation containing 1?mg tacrolimus for sublingual application. First, solid dispersions containing tacrolimus (2.5%, 5% and 10% w/w) incorporated in Ac-Di-Sol(?) and carriers (inulin 1.8?kDa and 4?kDa, and polyvinylpyrrolidone (PVP) K30) were prepared by freeze drying. Subsequently, a tablet formulation composed of a mixture of the solid dispersions, Ac-Di-Sol(?), mannitol, Avicel(?) PH-101 and sodium stearyl fumarate was optimized concerning drug load in the solid dispersions and the type of carrier. Tablet weight was kept constant at 75?mg by adjusting the amount of Avicel(?) PH-101. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) results indicated the absence of the drug in the crystalline state, which was confirmed by the scanning electron microscopy (SEM). These results suggest that tacrolimus incorporated in all of the solid dispersions was fully amorphous. Dissolution of the tablets containing solid dispersions with a low drug load highly depends on the type of carrier and increased in the order: PVP K30 < inulin 4?kDa < inulin 1.8?kDa. Solid dispersions with a drug load of 10% w/w incorporated in the carriers yielded optimal formulations. In addition, the physicochemical characteristics and the dissolution behavior of the tablet formulation containing inulin 1.8 kDa-based solid dispersions with a drug load of 10% w/w did not change after storage at 20°C/45%RH for 6 months indicating excellent storage stability.     

Comparative tablet and rheological properties of new microcrystalline cellulose: direct compression and wet granulation methods.

The overall objective of this study was to compare the rheological properties and tablet characteristics of two new varieties of celluloses (Vivacel 101 and 102), recently produced and commercialized, with the classical varieties of celluloses (Avicel and Elcema). The results showed no significant differences in the rheological properties of Vivacel and Avicel, while significant differences were found between the two celluloses and Elcema. Furthermore, there were no statistically significant differences in the disintegration times and Td values of Vivacel and Avicel. In conclusion, it was found that these new celluloses offer all the known advantages of Avicel.     

A study of the compaction process and the properties of tablets made of a new co-processed starch excipient

This article deals with the study of the energetic relationships during compaction and the properties of tablets produced from a co-processed excipient based on starch and called StarCap 1500?. This article compares it with the substance Starch1500?. The study also includes the mixtures of StarCap 1500? and the granulated directly compressible lactose Pharmatose DCL?15. The tablet properties tested included tensile strength and disintegration time, examined in dependence on compression force, and also a 0.4% addition of magnesium stearate. The results show a better compressibility of StarCap 1500 in comparison with Starch 1500 and a lower elastic component of energy. The tablets were stronger and disintegrated more rapidly, but the substance possessed a higher sensitivity to an addition of a lubricant than Starch 1500. Increasing portions of StarCap 1500 in the mixtures with Pharmatose DCL 15 increased the tensile strength of tablets, disintegration period as well as the sensitivity to an addition of a lubricant. From the energetic viewpoint, energy for friction was decreasing, while the energy accumulated by the tablet during compaction and the elastic component of energy were increased.     

A new formulation and computation of the triphasic model for mechano-electrochemical mixtures

From the generalized first law of thermodynamics for an irreversible thermodynamical system, a new set of governing equations for the mixture theory is derived based on the triphasic model for mechano-electrochemical mixtures. It is shown that, in the case of electroneutral solution, a new biphasic mixture theory including the electrochemical effects can be derived from the new governing equations. The chemical-expansion stress representing both the influences of deformation on the fixed charge density and the electric potential of fixed charge field is given. For comparison and verification purposes, the numerical solution for a confined compression problem of a charged hydrated soft tissue is computed using the multiquadric method. Received: 1 November 1998     

A study of the compaction process and the properties of tablets made of a new co-processed starch excipient

This article deals with the study of the energetic relationships during compaction and the properties of tablets produced from a co-processed excipient based on starch and called StarCap1500^®. This article compares it with the substance Starch1500^®. The study also includes the mixtures of StarCap 1500^® and the granulated directly compressible lactose Pharmatose DCL^®15. The tablet properties tested included tensile strength and disintegration time, examined in dependence on compression force, and also a 0.4% addition of magnesium stearate. The results show a better compressibility of StarCap 1500 in comparison with Starch 1500 and a lower elastic component of energy. The tablets were stronger and disintegrated more rapidly, but the substance possessed a higher sensitivity to an addition of a lubricant than Starch 1500. Increasing portions of StarCap 1500 in the mixtures with Pharmatose DCL 15 increased the tensile strength of tablets, disintegration period as well as the sensitivity to an addition of a lubricant. From the energetic viewpoint, energy for friction was decreasing, while the energy accumulated by the tablet during compaction and the elastic component of energy were increased.     

Nimesulide-modified gum karaya solid mixtures: preparation, characterization, and formulation development

Solid mixtures of nimesulide (NS) and modified gum karaya (MGK) were prepared to improve the dissolution rate of NS. The effect of drug-carrier ratio on dissolution rate of NS was investigated by preparing the solid mixtures of different ratios by cogrinding method. Solid mixtures were also prepared by physical mixing, kneading, and solid dispersion techniques to study the influence of method of preparation. Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD), and equilibrium solubility studies were performed to explain the results of in vitro dissolution rate studies. It was clearly evident from the results that the NS dissolution rate was dependent on the concentration of MGK in the solid mixtures, and optimum weight ratio was found to be 1:4 (NS:MGK). Though the dissolution rate of NS from all solid mixtures prepared by different methods improved significantly, maximum improvement in dissolution rate was observed with solid dispersions. The order of methods basing on their effect on dissolution efficiency is solid dispersion > kneading > cogrinding > physical mixing > pure NS. Tablets of pure drug and solid mixtures (1:4 w/w, NS:MGK) were prepared. Though the best results from the dissolution test were obtained for the tablets containing solid dispersions, tablets containing cogrinding mixture were found to be suitable, from a practical point of view, for commercialization.     

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 statistical analysis of Raman images of a pharmaceutical tablet

This paper describes the application of principal component analysis (PCA) and independent component analysis (ICA) to identify the reference spectra of a pharmaceutical tablet's constituent compounds from Raman spectroscopic data. The analysis shows, first with a simulated data set and then with data collected from a pharmaceutical tablet, that both PCA and ICA are able to identify most of the features present in the reference spectra of the constituent compounds. However, the results suggest that the ICA method may be more appropriate when attempting to identify unknown reference spectra from a sample. The resulting PCA and ICA models are subsequently used to estimate the relative concentrations of the constituent compounds and to produce spatial distribution images of the analyzed tablet. These images provide a visual representation of the spatial distribution of the constituent compounds throughout the tablet. Images associated with the ICA scores are found to be more informative and not as affected by measurement noise as the PCA based score images. The paper concludes with a discussion of the future work that needs to be undertaken for ICA to gain wider acceptance in the applied spectroscopy community.     

Characterization of khaya gum as a binder in a paracetamol tablet formulation

The influence of khaya gum, a binding agent obtained from Khaya grandifolia (Meliaceae family), on the bulk, compressional, and tabletting characteristics of a paracetamol tablet formulation was studied in comparison with the effects of two standard binders: polyvinylpyrrolidone (PVP; molecular weight 40,000) and gelatin. The relative ability of khaya gum to destroy any residual microbial contamination in the binder or in the formulation during tabletting was also studied using Bacillus subtilis spores as a model. Formulations containing khaya gum exhibited more densification than formulations containing PVP and gelatin during die filling, but less densification due to rearrangement at low pressures. The mean yield pressure of the formulation particles obtained from Heckel plots, and another pressure term, also inversely related to plasticity, obtained from Kawakita plots, showed dependence on the nature and concentration of the binder, with formulations containing khaya gum exhibiting the lowest and highest values respectively. The values of the pressure terms suggest that the yield pressure relates to the onset of plastic deformation during compression, while the Kawakita pressure relates to the total amount of plastic deformation occurring during the compression process. Tablets made from formulations containing khaya gum had the lowest tensile strength values but also the lowest tendency to laminate or cap, as indicated by their lowest brittleness. All the tablets had friability values < 1% at higher concentrations of the three binders. In addition, khaya gum demonstrated a comparable ability to destroy microorganisms in the formulation during tabletting as the two binders. The characterization of the formulations suggests that khaya gum can be developed into a commercial binding agent for particular tablets.     

An in vitro evaluation of fenugreek mucilage as a potential excipient for oral controlled-release matrix tablet

A polysaccharide mucilage derived from the seeds of fenugreek, Trigonella foenum-graceum L (family Fabaceae) was investigated for use in matrix formulations containing propranolol hydrochloride. Methocel^® hypomellose K4M was used as a standard controlled release polymer for comparison purposes. In this study the effect of lactose on the release behaviour of propranolol hydrochloride from matrices formulated to contain the fenugreek mucilage also was investigated. An increase in concentration of the mucilage in matrices resulted in a reduction in the release rate of propranolol hydrochloride comparable to that observed with hypomellose matrices. The rate of release of propranolol hydrochloride from fenugreek mucilage matrices was mainly controlled by the drug:mucilage ratio. However, the mechanism of release from matrices containing drug:mucilage ratios of 1:1, 1:1.25, 1:1.5, and 1:2 remained the same. The kinetics of release, utilising the release exponent n, showed that the values of n were between 0.46-0.57 indicating that the release from fenugreek mucilage matrices was predominantly by diffusion. The presence of lactose in matrices containing mucilage increased the release rate of propranolol hydrochloride. This is due to a reduction in tortuoisity and increased pore size of channels caused by lactose through which propranolol diffuses and therefore diffusion of water into the tablet is facilitated.     

Improved bioavailability of a micronized megestrol acetate tablet formulation in humans

Megestrol acetate, a progestogen widely used in the palliative treatment of endometrial carcinoma and breast cancer, is currently administered orally as a solid dosage form. Bioavailability of the drug following oral administration is closely related to the effectiveness and safety profile of the drug in formulation. Improved immediate-release formulations should allow improved drug delivery into the systemic circulation and, at the end, to the site of action. The micronization of drugs is one of the technological procedures to achieve such a purpose. This paper reports the design and results obtained in an in vivo study of the bioavailability of a micronized megestrol acetate tablet formulation compared to a conventional form. A significant increase in the drug bioavailability was observed, in either the rate or the extent of absorption. In vitro dissolution data of the two study formulations reflected the in vivo findings.     

The double-inclusion model: a new formulation and new estimates

A new version of the well-known double-inclusion model of Hori and Nemat-Nasser [Mech. Mater. 14 (1993) 189] is proposed in this work. First, the original model is reformulated in a general way dealing directly with multiphase composites. As in the case of two-phase composites, it is shown that the double-inclusion model includes as special cases some of the previously existing models. Finally, a new solution of the model is proposed that represents more closely the interactions in the material.     

Multivariate curve resolution and trilinear decomposition methods in the analysis of stopped-flow kinetic data for binary amino Acid mixtures

A stopped-flow method is proposed to carry out the kinetic development of the reaction between amino acids and 1,2-naphthoquinone-4-sulfonate by mixing analytes and reagent in a three-channel continuous-flow system. The process is monitored using a diode array spectrophotometer. Thus, every sample produces a data matrix built up from the spectra registered at regular steps of time. As the reaction is faster for secondary amino acids than for primary ones, it is possible to distinguish between the kinetic formation of their corresponding derivatives. The method is applied to the simultaneous determination of phenylalanine and proline by using second-order multivariate curve resolution. The derivatives of these two amino acids present some differences in both orders of measure, i.e., their spectra and kinetic profiles, which can be exploited advantageously to quantify one of the analytes in the presence of the other as interference, without including any information about this interference in the modeling of the system.     

Elastodynamics by BEM: a new direct formulation

A new direct BE formulation is proposed for the solution of elastodynamic problems. An analytical regularization procedure is devised via an integration‐by‐parts technique without introducing any hypothesis about either the discretization of the boundary geometry or the space–time interpolation of the elastic fields involved. The only requirement is for continuity in the displacement field. The regularization of the integral equations for static elasticity using the same approach, already available in the literature, is presented as a particular case of the general procedure introduced herein. The numerical implementation of this technique is discussed and two‐dimensional examples are presented. Copyright © 1999 John Wiley & Sons, Ltd.     

Chewability testing in the development of a chewable tablet for hyperphosphatemia

The official Pharmacopeia does not include a test procedure for the in vitro estimation of the chewability of tablets and publications in the scientific literature on this subject are rare. The purpose of this study was to evaluate a number of different test procedures for assessing chewability, starting from standard breaking force and strength testing and progressing to develop new procedures that simulate the actual chewing action on tablets. A further goal was to apply these test procedures to characterize the chewability of the novel phosphate binder PA21 in comparison with a commercially available phosphate binder chewable tablet product based on lanthanum (Fosrenol®) and a chewable tablet product containing calcium (Calcimagon®) – the latter being used as a standard for its very good chewability. For this purpose, a number of development formulations (different batches of PA21) were tested. The radial or diametrical tablet breaking force offers a poor means of assessing chewability while the axial breaking force was concluded to better reflect the effect of chewing on the tablet. Measurement of tablet behavior upon repeated loading afforded the best simulation of the actual chewing action and was found to have a good discriminating power with respect to chewability of the tested tablets, especially when the tablet was moistened with artificial saliva. The developed tests are shown to be more suitable for evaluating chewing properties of tablets than currently used Pharmacopeial tests. Following ICHQ6, which calls for specification of hardness for chewable tablets, these test procedures enabled the optimal chewability features of PA21 tablets in development to be confirmed whilst still maintaining capabilities for robust production and transportation processes.