Tablet Excipients Research Articles

Vapor Phase Alkyne Coating of Pharmaceutical Excipients: Discrimination Enhancement of Raman Chemical Imaging for Tablets

Raman chemical imaging has become a powerful analytical tool to investigate the crystallographic characteristics of pharmaceutical ingredients in tablet. However, it is often difficult to discriminate some pharmaceutical excipients from each other by Raman spectrum because of broad and overlapping signals, limiting their detailed assessments. To overcome this difficulty, we developed a vapor phase coating method of excipients by an alkyne, which exhibits a distinctive Raman signal in the range of 2100-2300 cm(-1) . We found that the combination of two volatile reagents, propargyl bromide and triethylamine, formed a thin and nonvolatile coating on the excipient and observed the Raman signal of the alkyne at the surface. We prepared alkyne-coated cellulose by this method and formed a tablet. The Raman chemical imaging of the tablet cross-section using the alkyne peak area intensity of 2120 cm(-1) as the index showed a much clearer particle image of cellulose than using the peak area intensity of 1370 cm(-1) , which originated from the cellulose itself. Our method provides an innovative technique to analyze the solid-state characteristics of pharmaceutical excipients in tablets.

Quantifying effects of moisture content on flow properties of microcrystalline cellulose using a ring shear tester

In this work, we have quantified effects of moisture content, over the relative humidity (RH) range of 5–92% corresponding to 1.6–10.9% of water content, on flow properties of a grade of microcrystalline cellulose (Avicel PH102) using a ring shear cell. Several key powder flow parameters, including cohesion (τc), unconfined yield strength (fc), powder bulk density (ρb), flowability (ffc), and effective angle of internal friction (ϕe), were assessed. Powder flow properties deteriorated continuously with increasing RH, as shown by the higher fc and τc as well as lower ffc, under all stress conditions. With increasing RH, ρb increased and then decreased with a maximum at 20% RH. The ϕe initially increased, from 41 to 43 degrees, and then remained approximately constant from 20% to 92% RH. The deterioration in powder flow properties is caused by surface modification by moisture, which enhances particle-particle interaction strength. The knowledge obtained in this study is useful to achieving consistent properties of this important tablet excipient and formulations containing it.

Development and validation of high performance liquid chromatographic method for the analysis of divalproex sodium

A high performance liquid chromatography method has been developed for the analysis of divalproex sodium in bulk and in its tablet formulation and spiked human plasma. The method utilized a Kromosil C18 reversed-phase analytical column (250 x 4.6 mm, particle size 5 µm) with 0.1% orthophosphoric acid and methanol (50:50 v/v ) as mobile phase. The analysis was performed at 30 0 C temperature with a flow rate of 1 ml/min and detection at 246 nm. The method was validated for specificity, sensitivity, precision, linearity, accuracy, selectivity and robustness. The method was found to be linear in the range between 6 μg/ml and 200 μg/ml with a correlation coefficient of 0.9998. The detection and quantitation limits obtained for DS were 0.298 μg/ml and 0.903 μg/ml, respectively. The specificity of the method was established through stress degradation studies. The results of stress degradation studies signify the stability indicating nature of the method. The developed method was applied effectively to tablet formulation and spiked human plasma without interference from the common excipients in tablets and endogenous substances in plasma.

Whey protein mucoadhesive properties for oral drug delivery: Mucin–whey protein interaction and mucoadhesive bond strength

Whey protein is a natural polymer recently used as an excipient in buccoadhesive tablets but its mucoadhesive properties were barely studied. In this work, we characterize mucoadhesion of whey protein in order to determine the mechanisms and optimal conditions for use as excipient in oral drug delivery. Thus, native and denatured whey protein (NWP and DWP) were investigated and the effect of concentration and pH were also studied. Many methods of characterization were selected to allow the study of chemical and physical interactions with mucin and then the results were bound with an ex vivo experiments. Turbidity of WP–mucin mixture increased at acidic pH 1.2 till 4.5 indicating interaction with mucin but not at pH 6.8. No interaction with mucin was also found by ITC method at pH 6.8 for native and denatured whey protein used at 1% (w/w). Forces of bioadhesion evaluated by viscosity measurements were the best for high concentrated (10.8%) DWP solutions at pH 6.8 and were low at pH 1.2 for NWP and DWP solutions. Addition of chemical blockers indicated that hydrogen bondings and disulfide bridges were the main mechanisms of interactions with mucin. Reticulation of DWP with calcium ions to obtain microparticles (MP) did not influence the ability of interaction with mucin as shown by FTIR analysis. These results correlated with ex vivo study on rat tissue demonstrating important adhesion (75%) of WP MP on the intestine and null on the stomach after 2h of deposit.

Development of Dispersible Self-microemulsifying Tablet of Atorvastatin

Aim: The aim of this study was to develop dispersible self-microemulsifying (SMEDDS) tablet of atorvastatin for promoting its solubility and thus its oral bioavailability. Materials and Methods: The liquid SMEDDS were prepared by water titration method using oil, surfactant and co-surfactant and converted into solid- SMEDDS (S-SMEDDS) by adsorption on solid carriers (Neusilin US2). The S-SMEDDS were blended with sodium starch glycolate (disintegrant) and tablet excipients and compressed into tablets that were dispersible and self-microemulsifying in nature. All these formulations were assessed for various physicochemical parameters viz. weight variation, hardness, friability, disintegration test. In vitro studies of pure drug, SMEDDS, S-SMEDDS and dispersible SME-tablets were carried out. Results: Pure drug released only 29.84 ± 0.16% upto 60 minutes and all the SMEDDS formulations (i.e. SMEDDS. S-SMEDDS and dispersible SME-tablets) released 100% of drug in comparatively lesser time. Formulations containing atorvastatin, 30% oleic acid, 65% tween 80 and 5% co-surfactant came out to show the best results in in vitro studies. But, FB1 (tablet) was considered to be the best since it released 100% drug in 35 min and also has advantages over SMEDDS and S-SMEDDS in terms of stability and patient compliance. Conclusion: The study revealed the potential use of dispersible SMEDDS tablet for the oral delivery of hydrophobic drugs, such as atorvastatin. Key words: Atorvastatin, Bioavailability, Phase diagram, SMEDDS.

A Stability Indicating HPLC Method for the Determination of Fluvoxamine in Pharmaceutical Dosage Forms.

Fluvoxamine maleate is a selective serotonin reuptake inhibitor, which is used for the treatment of different types of depressive disorders. In the present study, a stability indicating HPLC method was developed and validated for the determination of fluvoxamine maleate. The chromatographic separation was carried out using a Nova-Pak CN column and a mixture of K2HPO4 50 mM (pH 7.0) and acetonitrile (60: 40, v/v) as the mobile phase. Target compounds were detected using a UV detector set at 235 nm. The developed method was linear over the concentration range of 1-80 μg/ml with acceptable precision (CV values < 2.0%) and accuracy (error values < 1.6%). The degradation studies showed that fluvoxamine maleate is relatively unstable under acidic, basic and oxidative conditions and also when exposed to UV radiation. On the other hand, the bulk powder of fluvoxamine maleate was relatively stable when exposed to visible light or heat. The proposed method was successfully applied for the determination of active ingredient of fluvoxamine dosage form without any interference from tablet excipients.

A methodological evaluation and predictive in silico investigation into the multi-functionality of arginine in directly compressed tablets

The acceleration of solid dosage form product development can be facilitated by the inclusion of excipients that exhibit poly-/multi-functionality with reduction of the time invested in multiple excipient optimisations. Because active pharmaceutical ingredients (APIs) and tablet excipients present diverse densification behaviours upon compaction, the involvement of these different powders during compaction makes the compaction process very complicated. The aim of this study was to assess the macrometric characteristics and distribution of surface charges of two powders: indomethacin (IND) and arginine (ARG); and evaluate their impact on the densification properties of the two powders. Response surface modelling (RSM) was employed to predict the effect of two independent variables; Compression pressure (F) and ARG percentage (R) in binary mixtures on the properties of resultant tablets. The study looked at three responses namely; porosity (P), tensile strength (S) and disintegration time (T). Micrometric studies showed that IND had a higher charge density (net charge to mass ratio) when compared to ARG; nonetheless, ARG demonstrated good compaction properties with high plasticity (Y=28.01MPa). Therefore, ARG as filler to IND tablets was associated with better mechanical properties of the tablets (tablet tensile strength (σ) increased from 0.2±0.05N/mm2 to 2.85±0.36N/mm2 upon adding ARG at molar ratio of 8:1 to IND). Moreover, tablets’ disintegration time was shortened to reach few seconds in some of the formulations. RSM revealed tablet porosity to be affected by both compression pressure and ARG ratio for IND/ARG physical mixtures (PMs). Conversely, the tensile strength (σ) and disintegration time (T) for the PMs were influenced by the compression pressure, ARG ratio and their interactive term (FR); and a strong correlation was observed between the experimental results and the predicted data for tablet porosity. This work provides clear evidence of the multi-functionality of ARG as filler, binder and disintegrant for directly compressed tablets.

Tracking of crystalline-amorphous transition of carvedilol in rotary spun microfibers and their formulation to orodispersible tablets for in vitro dissolution enhancement

Physicochemical characterization of microfibers including powder X-ray diffraction, differential scanning calorimetry, attenuated total reflectance Fourier transform infrared spectroscopy, and positron annihilation spectroscopy were used to track the crystalline-amorphous transition of carvedilol during formulation and stability testing. The applied methods unanimously indicated the amorphous transition of carvedilol in the course of rotary spinning, furthermore a supramolecular ordering of chains of polymer matrix was revealed out by positron annihilation spectroscopy. The accelerated stability study (40±2°C/75±5% RH, for 4 weeks) indicated a large stress tolerance capacity of fibers, since only a partial crystallization of the active compound was observable at the last sampling point. To demonstrate possible utilization of microfibers, orodispersible tablets containing 10mg of carvedilol were successfully prepared by direct compression applying common tableting excipients. All of the investigated tablet parameters (hardness, friability, in vitro disintegration time) complied with the pharmacopoeial requirements. The performed dissolution (pH 1.0 and 6.8) study indicated that the drug dissolution from the microfiber based formula was rapid, complete and independent from the pH of the applied media, while the dissolution from the control tablets, containing crystalline carvedilol was incomplete and was strongly influenced by the pH of the applied media.

Determination of bosentan in pharmaceutical preparations by linear sweep, square wave and differential pulse voltammetry methods.

In this study, simple, fast and reliable cyclic voltammetry (CV), linear sweep voltammetry (LSV), square wave voltammetry (SWV) and differential pulse voltammetry (DPV) methods were developed and validated for determination of bosentan in pharmaceutical preparations. The proposed methods were based on electrochemical oxidation of bosentan at platinum electrode in acetonitrile solution containing 0.1 M TBACIO4. The well-defined oxidation peak was observed at 1.21 V. The calibration curves were linear for bosentan at the concentration range of 5-40µg/mL for LSV and 5-35µg/mL for SWV and DPV methods, respectively. Intra- and inter-day precision values for bosentan were less than 4.92, and accuracy (relative error) was better than 6.29%. The mean recovery of bosentan was 100.7% for pharmaceutical preparations. No interference was found from two tablet excipients at the selected assay conditions. Developed methods in this study are accurate, precise and can be easily applied to Tracleer and Diamond tablets as pharmaceutical preparation.

Diffusion and Swelling Measurements in Pharmaceutical Powder Compacts Using Terahertz Pulsed Imaging

Tablet dissolution is strongly affected by swelling and solvent penetration into its matrix. A terahertz-pulsed imaging (TPI) technique, in reflection mode, is introduced as a new tool to measure one-dimensional swelling and solvent ingress in flat-faced pharmaceutical compacts exposed to dissolution medium from one face of the tablet. The technique was demonstrated on three tableting excipients: hydroxypropylmethyl cellulose (HPMC), Eudragit RSPO, and lactose. Upon contact with water, HPMC initially shrinks to up to 13% of its original thickness before undergoing expansion. HPMC and lactose were shown to expand to up to 20% and 47% of their original size in 24 h and 13 min, respectively, whereas Eudragit does not undergo dimensional change. The TPI technique was used to measure the ingress of water into HPMC tablets over a period of 24 h and it was observed that water penetrates into the tablet by anomalous diffusion. X-ray microtomography was used to measure tablet porosity alongside helium pycnometry and was linked to the results obtained by TPI. Our results highlight a new application area of TPI in the pharmaceutical sciences that could be of interest in the development and quality testing of advanced drug delivery systems as well as immediate release formulations. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:1658–1667, 2015

Development and optimization of carvedilol orodispersible tablets: enhancement of pharmacokinetic parameters in rabbits.

BackgroundCarvedilol (CVD) is used for the treatment of essential hypertension, heart failure, and systolic dysfunction after myocardial infarction. Due to its lower aqueous solubility and extensive first-pass metabolism, the absolute bioavailability of CVD does not exceed 30%. To overcome these drawbacks, the objective of this work was to improve the solubility and onset of action of CVD through complexation with hydroxypropyl-β-cyclodextrin and formulation of the prepared complex as orodispersible tablets (ODTs).MethodsCompatibility among CVD and all tablet excipients using differential scanning calorimetry and Fourier transform infrared spectroscopy, complexation of CVD with different polymers, and determination of the solubility of CVD in the prepared complexes were first determined. A Box-Behnken design (BBD) was used to study the effect of tablet formulation variables on the characteristics of the prepared tablets and to optimize preparation conditions. According to BBD design, 15 formulations of CVD-ODTs were prepared by direct compression and then evaluated for their quality attributes. The relative pharmacokinetic parameters of the optimized CVD-ODTs were compared with those of the marketed CVD tablet. A single dose, equivalent to 2.5 mg/kg CVD, was administered orally to New Zealand white rabbits using a double-blind, randomized, crossover design.ResultsThe solubility of CVD was improved from 7.32 to 22.92 mg/mL after complexation with hydroxypropyl-β-cyclodextrin at a molar ratio of 1:2 (CVD to cyclodextrin). The formulated CVD-ODTs showed satisfactory results concerning tablet hardness (5.35 kg/cm2), disintegration time (18 seconds), and maximum amount of CVD released (99.72%). The pharmacokinetic data for the optimized CVD-ODT showed a significant (P<0.05) increase in maximum plasma concentration from 363.667 to 496.4 ng/mL, and a shortening of the time taken to reach maximum plasma concentration to 2 hours in comparison with the marketed tablet.ConclusionThe optimized CVD-ODTs showed improved oral absorption of CVD and a subsequent acceleration of clinical effect, which is favored for hypertensive and cardiac patients.

Xanthan gum: A versatile biopolymer for biomedical and technological applications

ABSTRACTXanthan gum is an extracellular polymer produced mainly by the bacteriumXanthomonas campestris. Traditionally it plays an important role in industrial applications as thickener, emulsion stabilizer and it has been added to water‐based drilling fluids due to its pseudoplastic behavior and thermal stability. The structural properties of xanthan in solution can be tuned by the temperature and ionic strength; under high ionic strength or low temperature, xanthan chains are arranged in helical conformation, whereas under low ionic strength or high temperature, xanthan chains are coiled. Xanthan high molecular weight favors the building up of physical and chemical networks, which have been used as carriers for drugs and proteins and as scaffolds for cells. In combination with other polymers xanthan has been applied as excipient in tablets or as supporting hydrogels for drug release applications, particularly due to its acid resistance. The large versatility of xanthan gum opens the possibility for the creation of new architectures and additional applications involving this fascinating polymer. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci.2015,132, 42035.

Synthesis and evaluation of the structural and physicochemical properties of carboxymethyl pregelatinized starch as a pharmaceutical excipient

A pregelatinized starch (PGS) was derivatized with sodium chloroacetate (SCA) in alcoholic medium under alkaline condition to produce carboxymethyl pregelatinized starch (CMPGS) with various degrees of substitution (DS). Influence of the molar ratio of SCA to the glucopyranose units (SCA/GU), reaction time, temperature and the amount of sodium hydroxide on the degree of substitution (DS) and the reaction efficiency (RE) was studied. An optimal concentration of 30% of NaOH, for a reaction time of 1h at 50°C and molar ratio (SCA/GU) equal to 1.0, yielded an optimal DS of 0.55 and a RE of 55%. SEM micrographs revealed that the carboxymethylation assigned the structural arrangement of CMPGS and caused the granular disintegration. Wide angle diffraction X-ray (XRD) showed that the crystallinity of starch was obviously varied after carboxymethylation. New bands in FTIR spectra at 1417 and 1603cm−1 indicated the presence of carboxymethyl groups. The solubility and viscosity of CMPGS increased with an increase in the degree of modification. In order to investigate the influence of DS on physical and drug release properties, CMPGS obtained with DS in the range of 0.12–0.55 was evaluated as tablet excipient for sustained drug release. Dissolution tests performed in phosphate buffer (pH 6.8), with Ibuprofen as drug model (25% loading) showed that CMPGS seems suitable to be used as sustained release excipient since the drug release was driven over a period up to 8h. The in vitro release kinetics studies revealed that all formulations fit well with Korsmeyer-Peppas model and the mechanism of drug release is non-Fickian diffusion.

Solid as Solvent- Novel Technique for Spectrophotometric Analysis of Ornidazole Tablets Using Melted Phenol as Solvent

Commonly used organic solvents for spectrophotometric analysis of water insoluble drugs include methanol, ethanol, chloroform, benzene, dichloromethane, dimethyl formamide, acetonitrile, ethyl acetate, toluene, carbon tetrachloride, acetone, hexane etc. The main drawbacks of organic solvents include high cost, toxicity and pollution. Organic solvents have numerous adverse effects caused by single exposure like dermatitis, headache, drowsiness, nausea, eye irritation and long term exposure causes serious effects such as neurological disorders, chronic renal failure, liver damage, necrosis, mutagenesis disorder. They should be replaced by other eco-friendly alternative sources. The present investigation is an attempt to show that solids can also be wisely used to act as solvent precluding the use of organic solvents. In a separate study, author has attempted soxhelation using phenol as solvent. The vapours of boiling phenol got condensed in extraction chamber to effect the extraction of active constituents from powder of crude drugs. The main objective of the present study is to demonstrate the solvent action of solids. Solid excipients can nicely be employed as solubilizers in the development of pharmaceutical dosage forms in solution form of poorly soluble drugs (mixed solvency concept). Present study describes the application of solvent character of melted phenol (at 50-60°C) for spectrophotometric estimation of ornidazole tablets. Solubility of ornidazole in distilled water is 8.03 mg/ml. More than 700 mg of ornidazole dissolves in one gram of melted phenol (at 50-60°C). In the present investigation, melted phenol (at 50-60°C) was utilized to extract out (dissolve) the drug from powder of ornidazole tablets. Distilled water was used for dilution purpose. Absorbances of standard solutions containing 5, 10, 15, 20 and 25 μg/ml were noted at 319 nm against reagent blanks to obtain calibration curve. Proposed method is novel, economic, eco-friendly, rapid, free from toxicity of organic solvent, accurate and reproducible. Recovery studies and statistical data proved the accuracy, reproducibility and precision of the proposed method. The presence of tablet excipients and phenol did not interfere in the spectrophotometric estimation at 319 nm. Phenol does not interfere in spectrophotometric estimation above 300 nm.

Determination of flurbiprofen in pharmaceutical preparations by GC–MS

This article describes a gas chromatography–mass spectrometry (GC–MS) method for the determination of flurbiprofen in pharmaceutical preparations. The method is based on the derivatization of flurbiprofen with N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA). For GC–MS, electron ionization mode (EI=70eV) and selected ion monitoring (SIM) mode were used for quantitative analysis (m/z 180 for flurbiprofen). Calibration curve was linear between the concentration range of 0.25–5.0μg/mL. Intra- and inter-day precision values for flurbiprofen were less than 3.64, and accuracy (relative error) was better than 2.67%. The mean recovery of flurbiprofen was 99.4% for pharmaceutical preparations. The limits of detection and quantification of flurbiprofen were 0.05 and 0.15μg/mL, respectively. No interference was found from tablet excipients at the selected assay conditions. Also, the method was applied for the quality control of five commercial flurbiprofen dosage forms to quantify the drug and to check the formulation content uniformity.

Evaluation, Formulation and Optimization Study of Myrrh (Commiphora myrrha) Resin as Rate Controlling Excipient in Sustained Release Matrix Tablets of Theophylline

Evaluation, Formulation and Optimization Study of Myrrh (Commiphora myrrha) Resin as Rate Controlling Excipient in Sustained Release Matrix Tablets of Theophylline

Estimation of Venlafaxine in Commercial Dosage Forms Using Simple and Convenient Spectrophotometric Method

Venlafaxine belongs to a group of Antidepressant with a novel chemical structure. In these studies describes a simple, accurate, precise and cost effective UV-visible spectrophotometric method for the estimation of Venlafaxine hydrochloride in bulk and pharmaceutical formulations. The method is based on the measurement of absorbance of Venlafaxine hydrochloride solution in 0.1N NaOH at 225 nm. The method obeys Beer's Lambert's law in the selected concentration range 5–25 μg/ml in selected solvent. The slope, intercept and correlation coefficient were also calculated. Results of percentage recovery study shows that the method was not affected by the presence of common excipients in tablets. The parameters like linearity, precision, accuracy were studied according to International Conference on Harmonization (ICH) guidelines. The developed method was validated in terms of accuracy, precision, linearity, limit of detection and limit of quantitation which proves suitability of proposed method for routine estimation of venlafaxine hydrochloride in bulk and pharmaceutical formulations.

Development and Validation of Spectrophotometric Method for Determination of Azelaic Acid

In these studies describes a simple, accurate, precise and cost effective UV-visible spectrophotometric method for the estimation of Azelaic acid in pure and pharmaceutical formulations. The method is based on the measurement of absorbance of Azelaic acid solution in Phosphate buffer pH 6.8 at 204nm in the wavelength range of 200-400nm. The method obeys Beer's Lambert's law in the selected concentration range10-50 μg/ml in selected media. The slope, intercept and correlation coefficient were also calculated. Results of percentage recovery study shows that the method was not affected by the presence of common excipients in tablets. The parameters like linearity, precision, accuracy, sensitivity study i.e. limit of detection and limit of quantitation were studied according to International Conference on Harmonization (ICH) guidelines. The developed method was validated in terms of accuracy, precision, linearity, limit of detection and limit of quantitation which proves suitability of proposed method for routine estimation of Azelaic acid in pure and pharmaceutical formulations.

Anodic Oxidation of Etodolac and its Linear Sweep, Square Wave and Differential Pulse Voltammetric Determination in Pharmaceuticals.

In this study, simple, fast and reliable cyclic voltammetry, linear sweep voltammetry, square wave voltammetry and differential pulse voltammetry methods were developed and validated for determination of etodolac in pharmaceutical preparations. The proposed methods were based on electrochemical oxidation of etodolac at platinum electrode in acetonitrile solution containing 0.1 M lithium perchlorate. The well-defined oxidation peak was observed at 1.03 V. The calibration curves were linear for etodolac at the concentration range of 2.5-50 μg/ml for linear sweep, square wave and differential pulse voltammetry methods, respectively. Intra- and inter-day precision values for etodolac were less than 4.69, and accuracy (relative error) was better than 2.00%. The mean recovery of etodolac was 100.6% for pharmaceutical preparations. No interference was found from three tablet excipients at the selected assay conditions. Developed methods in this study are accurate, precise and can be easily applied to Etol, Tadolak and Etodin tablets as pharmaceutical preparation.

Studi Pengaruh Bahan Tambahan pada Pola Puncak Kromatogram Tablet Parasetamol dengan Tlc-spektrofotodensitometri untuk Drug Profiling

The study of chromatogram peak pattern by influence of excipient in paracetamol tablet with TLC- Spectrophotodensitometry method for drug profiling has been done. Sample (6 kind of paracetamol tabletsfrom different factory) and reference compounds were analyzed with TB (cyclohexane : toluene:diethylamine = 75:15:10) and TAEA (toluene : acetone : ethanol: ammonia = 45:45:7:3) as mobile phase andAl-TLC Si 60 G F254 as stationary phase.The initial step was non analyte peak reduction on Al-TLC plate with washing method, drying time and temperature variation. Sample was extracted with 1 ml chloroform and Na2CO3 buffer pH 10 and spotted onAL-TLC plate. First, sample extract from same factory was spotted on one plate, continued by sample extractfrom 6 different factories on one plate which is replicated five fold on each plate that different. Plate was eluted and scanned at 210 nm. Chromatogram was analyzed by cosine and cluster function. C95 value thatwas calculated from sample was used as a parameter to determine the influence of excipient towardchromatogram peak pattern.The result of this research showed that each tablet from same factory gave C95 value near 100 if calculated with cosine function (96 - 98,7 for TB and 78 - 83 for TAEA), whereas if all tablets from 6different factories was used, the excipient from each tablet will give C95 value alteration (63 for TB and 68 for TAEA). Cluster analysis will divide sample into 3 different groups for TB and 1 group for TAEA.