This research paper examines the use of terahertz time-domain spectroscopy (THz-TDS) to determine the optical properties of pharmaceutical tablets as functions of porosity and active pharmaceutical ingredient (API) mass fraction. Four training sets of tablets with varying porosity, height, and API content were studied. The study found linear correlations between terahertz effective refractive index and both porosity and API mass fraction for the first time using real pharmaceutical tablets. These correlations could be useful for basic research and quality inspection of tablets. Additionally, a novel "optical strain" parameter was proposed based on THz measurements that provides information on both conventional mechanical strain and changes in solid material fill fraction during tablet compression.
RP-HPLC Method Developed for the Estimation of Etodolac and Thiocolchicoside ...ijtsrd
A new, simple, specific, sensitive, rapid, accurate and precise RP HPLC method was developed for the estimation of Etodolac ETO and Thiocolchicoside THIO in bulk and combined pharmaceutical dosage forms. Etodolac ETO and Thiocolchicoside THIO was chromatographed on a Symmetry ODS C18 4.6mm—250mm, 5µm Column in a mobile phase consisting of Acetonitrile Methanol Acetate Buffer 25 20 55 v v . The mobile phase was pumped at a flow rate of 1.0 ml min with detection at 238 nm. The detector response was linear in the concentration of 200 600µg ml 20 60µg ml for Etodolac and Thiocolchicoside respectively. The intra and inter day variation was found to be less than 2 . The mean recovery of the drug from the solution was 99.98 . The developed method was validated for sensitivity, accuracy, precision, ruggedness and robustness. The RSD results for precision and intermediate precision found less than 2.0 . The LOD and LOQ were found to be 0.86 and 1.18 µg ml for Etodolac and 2.4 and 3.54µg ml for Thiocolchicoside respectively. The proposed method is simple, fast, accurate, precise and reproducible hence it can be applied for routine quality control analysis of Etodolac ETO and Thiocolchicoside THIO in bulk and combined pharmaceutical formulations. Prapulla Putta "RP-HPLC Method Developed for the Estimation of Etodolac and Thiocolchicoside in Bulk and Combined Dosage Forms" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-4 | Issue-1 , December 2019, URL: https://www.ijtsrd.com/papers/ijtsrd29703.pdf Paper URL: https://www.ijtsrd.com/pharmacy/analytical-chemistry/29703/rp-hplc-method-developed-for-the-estimation-of-etodolac-and-thiocolchicoside-in-bulk-and-combined-dosage-forms/prapulla-putta
UV Spectrophotometric Method Development and Validation for Quantitative Esti...Sagar Savale
This document describes the development and validation of a UV spectrophotometric method for the quantitative estimation of paracetamol. Paracetamol was found to exhibit maximum absorption at 244 nm in methanol. The method was validated according to ICH guidelines and showed good linearity (R2 = 0.9999), recovery (99.78-100.54%), precision (<0.06% RSD), ruggedness (<0.02% RSD), and sensitivity (LOD = 0.37 μg/ml, LOQ = 0.98 μg/ml). The developed method is simple, rapid, economical and suitable for the analysis of paracetamol in bulk drug samples.
Development and Validation of RP HPLC Method for Estimation of Vortioxetine i...ijtsrd
A rapid and precise reverse phase high performance liquid chromatographic method has been developed for the validated of Vortioxetine in its pure form as well as in tablet dosage form. Chromatography was carried out on ODS C18 4.6 x 250 mm, 5µm column using Acetonitrile And Methonal 70 30 as the mobile phase at a flow rate of 1.0 mL min, the detection was carried out at 274nm. The retention time of the Vortioxetine was 2.922 ±0.02min. The method produce linear responses in the concentration range of 20 µg ml of Vortioxetine. The method precision for the determination of assay was below 2.0 RSD. The method is useful in the quality control of bulk and pharmaceutical formulations. Rathod K. G | Bargaje G. S | Rathod G. R | Deshpande O. V "Development and Validation of RP-HPLC Method for Estimation of Vortioxetine in Bulk and Pharmaceutical Dosage Form" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-3 | Issue-6 , October 2019, URL: https://www.ijtsrd.com/papers/ijtsrd28040.pdf Paper URL: https://www.ijtsrd.com/pharmacy/analytical-chemistry/28040/development-and-validation-of-rp-hplc-method-for-estimation-of-vortioxetine-in-bulk-and-pharmaceutical-dosage-form/rathod-k-g
UV Spectrophotometric Method Development And Validation For Quantitative Esti...Sagar Savale
U.V Spectrophotometric method have been widely employed in determination of Halcinonide in a mixture or fixed dose combination. For the ternary mixture containing Halcinonide, no spectrophotometric method for evaluation has been reported so far. Thus our aim is to develop method for Halcinonide estimation in ternary mixture using U.V spectrophotometry.
UV Spectrophotometric Method Development and Validation for Quantitative Esti...Sagar Savale
Aim: UV Spectrophotometric Method Development and Validation for quantitative estimation of
Diclofenac Sodium. Objective: U.V Spectrophotometric method have been widely employed for
determination of analyte in a mixture. Our aim is to develop spectroscopic method for estimation of the
diclofenac sodium in ternary mixture by using U.V spectrophotometry. Methodology: The method was
validated as per ICH guidelines. The recovery studies confirmed the accuracy and precision of the method.
Conclusion: It was successfully applied for the analysis of the drug in bulk and could be effectively used for
the routine analysis.
UV Spectrophotometric Method Development and Validation for Quantitative Esti...Sagar Savale
U.V Spectrophotometric method have been widely employed in determination of Curcumin in a mixture or fixed dose combination. For the ternary mixture containing Curcumin, no spectrophotometric method for evaluation has been reported so far. Thus our aim is to develop method for Curcumin estimation in ternary mixture using U.V spectrophotometry.
The document discusses matrix effects in LC-MS/MS bioanalysis. It describes how matrix effects can interfere with ionization and affect quantification accuracy and precision. Several techniques conferences have addressed this issue and recommended evaluating matrix effects during method development and validation. Common causes of matrix effects are phospholipids and endogenous compounds. Different sample extraction and processing techniques can minimize matrix effects to varying degrees, with solid phase extraction generally performing better than protein precipitation or liquid-liquid extraction. Addressing matrix effects is important for method reliability and reproducibility.
RP-HPLC Method Developed for the Estimation of Etodolac and Thiocolchicoside ...ijtsrd
A new, simple, specific, sensitive, rapid, accurate and precise RP HPLC method was developed for the estimation of Etodolac ETO and Thiocolchicoside THIO in bulk and combined pharmaceutical dosage forms. Etodolac ETO and Thiocolchicoside THIO was chromatographed on a Symmetry ODS C18 4.6mm—250mm, 5µm Column in a mobile phase consisting of Acetonitrile Methanol Acetate Buffer 25 20 55 v v . The mobile phase was pumped at a flow rate of 1.0 ml min with detection at 238 nm. The detector response was linear in the concentration of 200 600µg ml 20 60µg ml for Etodolac and Thiocolchicoside respectively. The intra and inter day variation was found to be less than 2 . The mean recovery of the drug from the solution was 99.98 . The developed method was validated for sensitivity, accuracy, precision, ruggedness and robustness. The RSD results for precision and intermediate precision found less than 2.0 . The LOD and LOQ were found to be 0.86 and 1.18 µg ml for Etodolac and 2.4 and 3.54µg ml for Thiocolchicoside respectively. The proposed method is simple, fast, accurate, precise and reproducible hence it can be applied for routine quality control analysis of Etodolac ETO and Thiocolchicoside THIO in bulk and combined pharmaceutical formulations. Prapulla Putta "RP-HPLC Method Developed for the Estimation of Etodolac and Thiocolchicoside in Bulk and Combined Dosage Forms" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-4 | Issue-1 , December 2019, URL: https://www.ijtsrd.com/papers/ijtsrd29703.pdf Paper URL: https://www.ijtsrd.com/pharmacy/analytical-chemistry/29703/rp-hplc-method-developed-for-the-estimation-of-etodolac-and-thiocolchicoside-in-bulk-and-combined-dosage-forms/prapulla-putta
UV Spectrophotometric Method Development and Validation for Quantitative Esti...Sagar Savale
This document describes the development and validation of a UV spectrophotometric method for the quantitative estimation of paracetamol. Paracetamol was found to exhibit maximum absorption at 244 nm in methanol. The method was validated according to ICH guidelines and showed good linearity (R2 = 0.9999), recovery (99.78-100.54%), precision (<0.06% RSD), ruggedness (<0.02% RSD), and sensitivity (LOD = 0.37 μg/ml, LOQ = 0.98 μg/ml). The developed method is simple, rapid, economical and suitable for the analysis of paracetamol in bulk drug samples.
Development and Validation of RP HPLC Method for Estimation of Vortioxetine i...ijtsrd
A rapid and precise reverse phase high performance liquid chromatographic method has been developed for the validated of Vortioxetine in its pure form as well as in tablet dosage form. Chromatography was carried out on ODS C18 4.6 x 250 mm, 5µm column using Acetonitrile And Methonal 70 30 as the mobile phase at a flow rate of 1.0 mL min, the detection was carried out at 274nm. The retention time of the Vortioxetine was 2.922 ±0.02min. The method produce linear responses in the concentration range of 20 µg ml of Vortioxetine. The method precision for the determination of assay was below 2.0 RSD. The method is useful in the quality control of bulk and pharmaceutical formulations. Rathod K. G | Bargaje G. S | Rathod G. R | Deshpande O. V "Development and Validation of RP-HPLC Method for Estimation of Vortioxetine in Bulk and Pharmaceutical Dosage Form" Published in International Journal of Trend in Scientific Research and Development (ijtsrd), ISSN: 2456-6470, Volume-3 | Issue-6 , October 2019, URL: https://www.ijtsrd.com/papers/ijtsrd28040.pdf Paper URL: https://www.ijtsrd.com/pharmacy/analytical-chemistry/28040/development-and-validation-of-rp-hplc-method-for-estimation-of-vortioxetine-in-bulk-and-pharmaceutical-dosage-form/rathod-k-g
UV Spectrophotometric Method Development And Validation For Quantitative Esti...Sagar Savale
U.V Spectrophotometric method have been widely employed in determination of Halcinonide in a mixture or fixed dose combination. For the ternary mixture containing Halcinonide, no spectrophotometric method for evaluation has been reported so far. Thus our aim is to develop method for Halcinonide estimation in ternary mixture using U.V spectrophotometry.
UV Spectrophotometric Method Development and Validation for Quantitative Esti...Sagar Savale
Aim: UV Spectrophotometric Method Development and Validation for quantitative estimation of
Diclofenac Sodium. Objective: U.V Spectrophotometric method have been widely employed for
determination of analyte in a mixture. Our aim is to develop spectroscopic method for estimation of the
diclofenac sodium in ternary mixture by using U.V spectrophotometry. Methodology: The method was
validated as per ICH guidelines. The recovery studies confirmed the accuracy and precision of the method.
Conclusion: It was successfully applied for the analysis of the drug in bulk and could be effectively used for
the routine analysis.
UV Spectrophotometric Method Development and Validation for Quantitative Esti...Sagar Savale
U.V Spectrophotometric method have been widely employed in determination of Curcumin in a mixture or fixed dose combination. For the ternary mixture containing Curcumin, no spectrophotometric method for evaluation has been reported so far. Thus our aim is to develop method for Curcumin estimation in ternary mixture using U.V spectrophotometry.
The document discusses matrix effects in LC-MS/MS bioanalysis. It describes how matrix effects can interfere with ionization and affect quantification accuracy and precision. Several techniques conferences have addressed this issue and recommended evaluating matrix effects during method development and validation. Common causes of matrix effects are phospholipids and endogenous compounds. Different sample extraction and processing techniques can minimize matrix effects to varying degrees, with solid phase extraction generally performing better than protein precipitation or liquid-liquid extraction. Addressing matrix effects is important for method reliability and reproducibility.
UV Spectrophotometric Method Development and Validation for Quantitative Esti...Sagar Savale
UV Spectrophotometric Method Development and Validation for quantitative estimation of Miconazole nitrate
(MIC). U.V Spectrophotometric method have been widely employed in determination of individual components in
a mixture or fixed dose combination. Our aim is to develop spectroscopic method for estimation of the Miconazole
nitrate (MIC) in ternary mixture by using U.V spectrophotometry. The method was validated as per ICH
guidelines. The recovery studies confirmed the accuracy and precision of the method. It was successfully applied
for the analysis of the drug in bulk and could be effectively used for the routine analysis.
Differential spectrophotometric method for estimation and validation of Verap...roshan telrandhe
The aimed of current research to development of the simple, rapid and sensitive Differential spectrophotometric method for the estimation of Verapamil in tablet dosage form. In this method two medium was use acid and alkaline and the difference spectrum was calculated. 0.1N HCL and 0.1N NaOH was used in this differential method. The λmax 278, beeers law limits 525µg/ml, regression equation Y= 0.024x-0.009, slope 0.024, intercept 0.09, correlation coefficient (r2) 0.998, %RSD <1.5, % Recovery (Tablet) 100.46% was shows the good efficacy and results. This method future scope in quality control of the verapamine in simple, precise and economically and it recommended for the routine drug quality analysis investigation.
To perform Analytical method validation of Paracetamol Tablets by UV-spectrop...Aakashdeep Raval
This document outlines the validation of an analytical method for the quantification of paracetamol using UV spectrophotometry. It describes the validation parameters that will be tested which include accuracy, precision, linearity, range, limit of detection and limit of quantification, selectivity and specificity, and robustness and ruggedness. The procedure involves preparing calibration standards of paracetamol to generate a linear curve and then testing the method's accuracy by spiking samples. Precision will be evaluated by repeatability, intraday, and interday testing. The document provides the theory and equations needed to calculate the validation parameters.
Simultaneous determination of paracetamol and diphenhydramine hydrochloride m...IOSR Journals
New accurate, selective, sensitive and precise methods were developed and validated for
determination of paracetamol and diphenhydramine hydrochloride in the presence of P-amino phenol, the
hydrolytic degradate and the most potential impurity of paracetamol and the N oxide degradation product of
diphenhydramine in bulk form and in pharmaceutical formulation.Method A uses double divisor second
derivative of ratio spectrophotometric technique, at 304nm for paracetamol and 256.4nm for diphenhydramine
hydrochloride. Method B utilizes Principle Component Regression (PCR) and Partial Least Squares (PLS)
chemometric techniques for quantification of the four components using a UV spectrum range of 210-350 nm.
The proposed methods were successfully applied to the analysis of the mentioned drugs either in bulk powder or
in pharmaceutical formulation without interference from other dosage form additives, and the results were
statistically compared with the pharmacopoeial method.
This document discusses optimization techniques used in pharmaceutical development. It defines optimization as choosing the best alternative from available options to make something as perfect or effective as possible. It discusses various optimization parameters like problem type (constrained vs unconstrained), variables (independent vs dependent), and methods like response surface methodology, factorial designs, evolutionary operations, and search methods. Response surface methodology uses statistical experimental designs like central composite designs to determine the relationship between independent and dependent variables and find the optimum formulation.
This document summarizes various mathematical models used to analyze drug release kinetics from pharmaceutical dosage forms. It discusses the Higuchi, Korsmeyer-Peppas, and difference factor (f1) and similarity factor (f2) models. The Higuchi model describes drug release from a matrix based on square root of time. The Korsmeyer-Peppas model characterizes drug release mechanisms based on the release exponent n value. The f1 and f2 factors are used to compare dissolution profiles between two drug products.
This document summarizes an article that examines how different ionization source designs in LC-ESI-MS/MS systems can influence matrix effects during analysis. The article analyzes acamprosate (ACM) using two different LC-ESI-MS/MS instruments with different ionization source designs (a Z-spray source and an orthogonal spray source) coupled to UPLC/HPLC systems under the same chromatographic conditions. It finds that ACM showed almost complete ion suppression in the Z-spray source coupled to UPLC/HPLC, but only minor ion enhancement in the orthogonal spray source coupled to HPLC. Different phospholipids were responsible for the matrix effects in each case. The study demonstrates how
This document discusses instrumental methods of analysis used for qualitative and quantitative analysis of drugs. It describes the scope, objectives, types of analysis, and applications of instrumental analysis. The objectives are to understand interactions of matter with electromagnetic radiation and its applications in drug analysis, understand chromatographic separation and analysis of drugs, and perform quantitative and qualitative drug analysis using analytical instruments. Types of analysis include classical wet chemical methods and modern instrumental methods using techniques like chromatography, spectroscopy, and electrophoresis. Applications include biomedical analysis, pharmaceutical quality control, environmental monitoring, and forensic science.
This document describes the development and validation of a new reverse phase high performance liquid chromatography (RP-HPLC) method for the estimation of paracetamol in pharmaceutical dosage forms. Some key points:
- An isocratic RP-HPLC method was developed using a mobile phase of acetonitrile and potassium dihydrogen orthophosphate buffer at a ratio of 15:85, pH 2.5.
- The method was validated for parameters such as linearity, accuracy, precision, limit of detection, limit of quantification, and robustness as per ICH guidelines.
- The method showed good linearity in the range of 25-60 μg/ml with a correlation coefficient of 0.999
This document describes the development and validation of a UV spectrophotometric method for the estimation of methocarbamol in bulk and pharmaceutical dosage forms. The method was developed using acetone and 0.1N sodium hydroxide solution as solvents, in which methocarbamol is soluble. The drug has maximum absorbance at 267 nm. The method was validated as per ICH guidelines and was found to be linear, precise, accurate and specific. The developed method can be used for the quantitative analysis of methocarbamol in bulk and pharmaceutical formulations.
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
All manuscripts are subject to rapid peer review. Those of high quality (not previously published and not under consideration for publication in another journal) will be published without delay.
UV Spectroscopic Assay Method Development and Validation of Amoxicillin in ...Imran al
UV Spectroscopic Assay Method Development and Validation of Amoxicillin in Tablet Formulation in 3 different brand tablet formulations used in Bangladesh
The document discusses matrix effects, which occur when components in biological samples interfere with the ionization process during mass spectrometry analysis, potentially enhancing or suppressing the signal of the analyte. Matrix effects can negatively impact accuracy, precision, and detection limits. Two types of matrix effects are described - qualitative effects seen through post-column infusion experiments and quantitative effects evaluated by measuring the matrix factor. Approaches to minimize matrix effects include optimizing extraction and chromatography procedures, using stable isotope internal standards, and selecting an APCI ionization source instead of ESI when possible.
The document discusses different analytical techniques used to analyze drug-excipient interactions, including thermogravimetric analysis (TGA), differential thermal analysis (DTA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and FT-IR spectroscopy. Each technique is described in one to two sentences. TGA measures mass changes as temperature changes and provides information on physical and chemical phenomena like decomposition. DTA and DSC measure the temperature and heat flow differences between a sample and reference to determine endothermic and exothermic reactions like melting. XRD analyzes diffraction patterns to characterize crystal structure and polymorphism. FT-IR identifies functional groups and structures by analyzing absorption peaks.
Application of Terahertz spectroscopy in pharmaceutical industryPravin Medtiya
This document provides an overview of terahertz spectroscopy. It discusses the principle, instrumentation, advantages, and applications of terahertz spectroscopy. Three case studies are presented that demonstrate applications in pharmaceutical analysis: (1) distinguishing enantiomers of amino acids, (2) correlating terahertz measurements of tablet porosity and density to disintegration time, and (3) using terahertz spectroscopy to better distinguish between crystalline and amorphous forms of drugs compared to Raman spectroscopy. The document concludes that terahertz spectroscopy has enabled various pharmaceutical applications and has potential for high throughput drug development and medical diagnostics.
Design expert software assisted development and evaluation of cefpodoxime pro...Makrani Shaharukh
This document describes a study that developed and evaluated sustained release matrix tablets of the antibiotic drug Cefpodoxime Proxetil using natural polymers like karaya gum and acacia gum. 32 factorial designs were used to optimize the tablet formulations and evaluate the effect of polymer concentration on tablet properties like hardness and drug release. Tablets were prepared by direct compression and evaluated for drug-polymer compatibility, pre-compression parameters, post-compression parameters, in-vitro drug release, release kinetics, and stability. The optimized formulation F5 showed sustained drug release over 12 hours and maintained stability over time, indicating these matrix tablets could improve the oral bioavailability of Cefpodoxime Proxetil.
UV Spectrophotometric Method Development and Validation for Quantitative Esti...Sagar Savale
UV Spectrophotometric Method Development and Validation for quantitative estimation of Miconazole nitrate
(MIC). U.V Spectrophotometric method have been widely employed in determination of individual components in
a mixture or fixed dose combination. Our aim is to develop spectroscopic method for estimation of the Miconazole
nitrate (MIC) in ternary mixture by using U.V spectrophotometry. The method was validated as per ICH
guidelines. The recovery studies confirmed the accuracy and precision of the method. It was successfully applied
for the analysis of the drug in bulk and could be effectively used for the routine analysis.
Differential spectrophotometric method for estimation and validation of Verap...roshan telrandhe
The aimed of current research to development of the simple, rapid and sensitive Differential spectrophotometric method for the estimation of Verapamil in tablet dosage form. In this method two medium was use acid and alkaline and the difference spectrum was calculated. 0.1N HCL and 0.1N NaOH was used in this differential method. The λmax 278, beeers law limits 525µg/ml, regression equation Y= 0.024x-0.009, slope 0.024, intercept 0.09, correlation coefficient (r2) 0.998, %RSD <1.5, % Recovery (Tablet) 100.46% was shows the good efficacy and results. This method future scope in quality control of the verapamine in simple, precise and economically and it recommended for the routine drug quality analysis investigation.
To perform Analytical method validation of Paracetamol Tablets by UV-spectrop...Aakashdeep Raval
This document outlines the validation of an analytical method for the quantification of paracetamol using UV spectrophotometry. It describes the validation parameters that will be tested which include accuracy, precision, linearity, range, limit of detection and limit of quantification, selectivity and specificity, and robustness and ruggedness. The procedure involves preparing calibration standards of paracetamol to generate a linear curve and then testing the method's accuracy by spiking samples. Precision will be evaluated by repeatability, intraday, and interday testing. The document provides the theory and equations needed to calculate the validation parameters.
Simultaneous determination of paracetamol and diphenhydramine hydrochloride m...IOSR Journals
New accurate, selective, sensitive and precise methods were developed and validated for
determination of paracetamol and diphenhydramine hydrochloride in the presence of P-amino phenol, the
hydrolytic degradate and the most potential impurity of paracetamol and the N oxide degradation product of
diphenhydramine in bulk form and in pharmaceutical formulation.Method A uses double divisor second
derivative of ratio spectrophotometric technique, at 304nm for paracetamol and 256.4nm for diphenhydramine
hydrochloride. Method B utilizes Principle Component Regression (PCR) and Partial Least Squares (PLS)
chemometric techniques for quantification of the four components using a UV spectrum range of 210-350 nm.
The proposed methods were successfully applied to the analysis of the mentioned drugs either in bulk powder or
in pharmaceutical formulation without interference from other dosage form additives, and the results were
statistically compared with the pharmacopoeial method.
This document discusses optimization techniques used in pharmaceutical development. It defines optimization as choosing the best alternative from available options to make something as perfect or effective as possible. It discusses various optimization parameters like problem type (constrained vs unconstrained), variables (independent vs dependent), and methods like response surface methodology, factorial designs, evolutionary operations, and search methods. Response surface methodology uses statistical experimental designs like central composite designs to determine the relationship between independent and dependent variables and find the optimum formulation.
This document summarizes various mathematical models used to analyze drug release kinetics from pharmaceutical dosage forms. It discusses the Higuchi, Korsmeyer-Peppas, and difference factor (f1) and similarity factor (f2) models. The Higuchi model describes drug release from a matrix based on square root of time. The Korsmeyer-Peppas model characterizes drug release mechanisms based on the release exponent n value. The f1 and f2 factors are used to compare dissolution profiles between two drug products.
This document summarizes an article that examines how different ionization source designs in LC-ESI-MS/MS systems can influence matrix effects during analysis. The article analyzes acamprosate (ACM) using two different LC-ESI-MS/MS instruments with different ionization source designs (a Z-spray source and an orthogonal spray source) coupled to UPLC/HPLC systems under the same chromatographic conditions. It finds that ACM showed almost complete ion suppression in the Z-spray source coupled to UPLC/HPLC, but only minor ion enhancement in the orthogonal spray source coupled to HPLC. Different phospholipids were responsible for the matrix effects in each case. The study demonstrates how
This document discusses instrumental methods of analysis used for qualitative and quantitative analysis of drugs. It describes the scope, objectives, types of analysis, and applications of instrumental analysis. The objectives are to understand interactions of matter with electromagnetic radiation and its applications in drug analysis, understand chromatographic separation and analysis of drugs, and perform quantitative and qualitative drug analysis using analytical instruments. Types of analysis include classical wet chemical methods and modern instrumental methods using techniques like chromatography, spectroscopy, and electrophoresis. Applications include biomedical analysis, pharmaceutical quality control, environmental monitoring, and forensic science.
This document describes the development and validation of a new reverse phase high performance liquid chromatography (RP-HPLC) method for the estimation of paracetamol in pharmaceutical dosage forms. Some key points:
- An isocratic RP-HPLC method was developed using a mobile phase of acetonitrile and potassium dihydrogen orthophosphate buffer at a ratio of 15:85, pH 2.5.
- The method was validated for parameters such as linearity, accuracy, precision, limit of detection, limit of quantification, and robustness as per ICH guidelines.
- The method showed good linearity in the range of 25-60 μg/ml with a correlation coefficient of 0.999
This document describes the development and validation of a UV spectrophotometric method for the estimation of methocarbamol in bulk and pharmaceutical dosage forms. The method was developed using acetone and 0.1N sodium hydroxide solution as solvents, in which methocarbamol is soluble. The drug has maximum absorbance at 267 nm. The method was validated as per ICH guidelines and was found to be linear, precise, accurate and specific. The developed method can be used for the quantitative analysis of methocarbamol in bulk and pharmaceutical formulations.
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
All manuscripts are subject to rapid peer review. Those of high quality (not previously published and not under consideration for publication in another journal) will be published without delay.
UV Spectroscopic Assay Method Development and Validation of Amoxicillin in ...Imran al
UV Spectroscopic Assay Method Development and Validation of Amoxicillin in Tablet Formulation in 3 different brand tablet formulations used in Bangladesh
The document discusses matrix effects, which occur when components in biological samples interfere with the ionization process during mass spectrometry analysis, potentially enhancing or suppressing the signal of the analyte. Matrix effects can negatively impact accuracy, precision, and detection limits. Two types of matrix effects are described - qualitative effects seen through post-column infusion experiments and quantitative effects evaluated by measuring the matrix factor. Approaches to minimize matrix effects include optimizing extraction and chromatography procedures, using stable isotope internal standards, and selecting an APCI ionization source instead of ESI when possible.
The document discusses different analytical techniques used to analyze drug-excipient interactions, including thermogravimetric analysis (TGA), differential thermal analysis (DTA), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), and FT-IR spectroscopy. Each technique is described in one to two sentences. TGA measures mass changes as temperature changes and provides information on physical and chemical phenomena like decomposition. DTA and DSC measure the temperature and heat flow differences between a sample and reference to determine endothermic and exothermic reactions like melting. XRD analyzes diffraction patterns to characterize crystal structure and polymorphism. FT-IR identifies functional groups and structures by analyzing absorption peaks.
Application of Terahertz spectroscopy in pharmaceutical industryPravin Medtiya
This document provides an overview of terahertz spectroscopy. It discusses the principle, instrumentation, advantages, and applications of terahertz spectroscopy. Three case studies are presented that demonstrate applications in pharmaceutical analysis: (1) distinguishing enantiomers of amino acids, (2) correlating terahertz measurements of tablet porosity and density to disintegration time, and (3) using terahertz spectroscopy to better distinguish between crystalline and amorphous forms of drugs compared to Raman spectroscopy. The document concludes that terahertz spectroscopy has enabled various pharmaceutical applications and has potential for high throughput drug development and medical diagnostics.
Design expert software assisted development and evaluation of cefpodoxime pro...Makrani Shaharukh
This document describes a study that developed and evaluated sustained release matrix tablets of the antibiotic drug Cefpodoxime Proxetil using natural polymers like karaya gum and acacia gum. 32 factorial designs were used to optimize the tablet formulations and evaluate the effect of polymer concentration on tablet properties like hardness and drug release. Tablets were prepared by direct compression and evaluated for drug-polymer compatibility, pre-compression parameters, post-compression parameters, in-vitro drug release, release kinetics, and stability. The optimized formulation F5 showed sustained drug release over 12 hours and maintained stability over time, indicating these matrix tablets could improve the oral bioavailability of Cefpodoxime Proxetil.
The document discusses comparison of dissolution profiles through different methods and establishing an IVIVC (in vitro-in vivo correlation). It provides definitions of dissolution profile and objectives of comparing profiles. Various methods for comparing profiles are described, including graphical, statistical, and model-dependent/independent methods. Key factors for determining similarity between dissolution profiles using statistical methods like difference factor and similarity factor are outlined. The importance of developing an IVIVC to reduce costs and the need for bioavailability studies is also mentioned. A research article comparing different brands of metformin tablets using tests like dissolution rate, drug content and disintegration is briefly summarized.
This document provides an overview of preformulation studies for developing pharmaceutical dosage forms. It discusses the need for dosage forms and outlines various preformulation parameters including physical characteristics like organoleptic properties, bulk characteristics, solubility analysis, and stability analysis. It also discusses chemical characteristics and techniques for identifying polymorphism. The goal of preformulation studies is to generate information to help formulators develop stable and bioavailable dosage forms that can be mass produced.
This document discusses dissolution profile comparison methods. It begins with introducing dissolution profiles and their importance in evaluating drug release from formulations. The objectives of comparing dissolution profiles are outlined, such as developing in vitro-in vivo correlations. Graphical, statistical, and model-dependent/independent methods for comparing profiles are described. The most commonly used model-independent methods, difference factor (f1) and similarity factor (f2), are explained in detail.
Evaluation methods for drug excipients and container interactionSagar Savale
This document discusses drug-excipient interactions, including the types (drug-excipient, drug-drug, excipient-excipient, drug-container), mechanisms (physical, chemical, physiological), and methods of evaluation such as differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and Fourier transform infrared spectroscopy (FTIR). DSC is used to study thermal transitions like melting points and glass transition temperatures to detect interactions. XRPD provides information on crystalline structure and changes from interactions. FTIR detects changes in molecular vibrations from interactions. Together these methods help evaluate excipient compatibility and identify interactions.
Non Destructive Air Coupled Acoustics AapsDipankar Dey
A noncontact/nondestructive air-coupled acoustic technique to be potentially used in
mechanical property determination of bilayer tablets is presented. In the reported experiments, a bilayer
tablet is vibrated via an acoustic field of an air-coupled transducer in a frequency range sufficiently high
to excite several vibrational modes (harmonics) of the tablet. The tablet vibrational transient responses at
a number of measurement points on the tablet are acquired by a laser vibrometer in a noncontact
manner. An iterative computational procedure based on the finite element method is utilized to extract
the Young’s modulus, the Poisson’s ratio, and the mass density values of each layer material of a bilayer
tablet from a subset of the measured resonance frequencies. For verification purposes, a contact
ultrasonic technique based on the time-of-flight data of the longitudinal (pressure) and transverse (shear)
acoustic waves in each layer of a bilayer tablet is also utilized. The extracted mechanical properties from
the air-coupled acoustic data agree well with those determined from the contact ultrasonic measurements.
The mechanical properties of solid oral dosage forms have been shown to impact its mechanical
integrity, disintegration profile and the release rate of the drug in the digestive tract, thus potentially
affecting its therapeutic response. The presented nondestructive technique provides greater insight into
the mechanical properties of the bilayer tablets and has the potential to identify quality and performance
problems related to the mechanical properties of the bilayer tablets early on the production process and,
consequently, reduce associated cost and material waste.
KEY WORDS:
This document discusses replacing the thorough QT (TQT) study with early QT assessment using data from first-in-human single and multiple ascending dose studies. Exposure-response modeling can be applied to QT interval data from early studies to assess for effects on QTc prolongation. Two examples are provided where early QT assessment identified a compound with no effect and another with a significant effect. While early assessment provides higher power than traditional time-matched analysis, challenges remain around demonstrating assay sensitivity without a pharmacological positive control in early studies. Further research is needed to generate data supporting replacement of the TQT study.
This document discusses replacing the thorough QT (TQT) study with early QT assessment using data from first-in-human single and multiple ascending dose studies. Exposure-response modeling can be applied to QT interval data from early studies to characterize a drug's effects on QT prolongation. Two examples are provided where this approach successfully identified a drug with no QT effect and a drug with a significant QT effect. While early QT assessment has potential advantages, challenges include demonstrating assay sensitivity without a pharmacological positive control in smaller early studies. Further research is needed but early assessment may provide sufficient data to replace the TQT study in some cases.
Bioequivalence studies ( Evaluation and Study design)Selim Akhtar
The document discusses various aspects of bioequivalence studies including study designs and evaluation. It describes four main study designs - pilot studies, replicate designs, non-replicate designs, and food-effect studies. It also discusses evaluating bioequivalence through comparative pharmacokinetic studies, pharmacodynamic studies, clinical trials, in vitro dissolution testing, and other approaches. The key aspects covered are parameters for determining bioequivalence like AUC and Cmax, study considerations for highly variable drugs, and the role of in vitro tests in bioequivalence assessments.
Modern p'ceutics drug excipient interactionArjunDhawale
This document discusses drug excipient interactions and stability testing methods. It covers various methods to detect drug-excipient compatibility, including thermal methods like DSC and TGA, spectroscopic techniques like FT-IR and PXRD, chromatography methods like HPLC and TLC, and microscopic techniques like SEM. It also discusses kinetics of stability including zero-order kinetics and half-life calculations. The goal is to understand interactions between drugs and excipients that can impact stability and shelf life through accelerated stability studies and various analytical techniques.
Crimson Publishers: Reply To: Comments on "Transabdominal Preperitoneal (TAPP...CrimsonGastroenterology
Reply To: Comments on “Transabdominal Preperitoneal (TAPP) Versus Totally Extraperitoneal (TEP) for Laparoscopic Hernia Repair: A Meta-Analysis” by Feng Xian Wei in Gastroenterology Medicine & Research
An in vitro – in vivo correlation (IVIVC) is defined by the U.S Food and Drug Administration (FDA) as a predictive mathematical model describing the relationship between the in vitro property of an oral dosage form and relevant in vivo response.
IN-VITRO-IN VIVO CORRELATION (IVIVC).pptxRAHUL PAL
An in vitro – in vivo correlation (IVIVC) is defined by the U.S Food and Drug Administration (FDA) as a predictive mathematical model describing the relationship between the in vitro property of an oral dosage form and relevant in vivo response.
Acta Biomaterialia 49 (2017) 402–413
Contents lists available at ScienceDirect
Acta Biomaterialia
journal homepage: www.elsevier.com/locate/actabiomat
Full length article
Programmed near-infrared light-responsive drug delivery system for
combined magnetic tumor-targeting magnetic resonance imaging and
chemo-phototherapy
http://dx.doi.org/10.1016/j.actbio.2016.11.035
1742-7061/� 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
⇑ Corresponding authors at: School of Pharmaceutical Sciences, Zhengzhou
University, 100 Kexue Avenue, Zhengzhou 450001, China.
E-mail addresses: [email protected] (L. Hou), [email protected]
(Z. Zhang).
Qianhua Feng a,b,c, Yuanyuan Zhang a, Wanxia Zhang a, Yongwei Hao a,b,c, Yongchao Wang a,b,c,
Hongling Zhang a,b,c, Lin Hou a,b,c,⇑, Zhenzhong Zhang a,b,c,⇑
a School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou 450001, China
b Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Zhengzhou 450001, China
c Key Laboratory of Targeting Therapy and Diagnosis for Critical Diseases, Henan Province, Zhengzhou 450001, China
a r t i c l e i n f o
Article history:
Received 15 July 2016
Received in revised form 3 November 2016
Accepted 15 November 2016
Available online 24 November 2016
Keywords:
Hollow mesoporous copper sulfide
Magnetic targeting
Controlled release
Theranostics
a b s t r a c t
In this study, an intelligent drug delivery system was developed by capping doxorubicin (DOX)-loaded
hollow mesoporous CuS nanoparticles (HMCuS NPs) with superparamagnetic iron oxide nanoparticles
(IONPs). Under near infrared (NIR) light irradiation, the versatile HMCuS NPs could exploit the merits
of both photothermal therapy (PTT) and photodynamic therapy (PDT) simultaneously. Herein, the mul-
tifunctional IONPs as gatekeeper with the enhanced capping efficiency were supposed to realize ‘‘zero
premature release” and minimize the adverse side effects during the drug delivery in vivo. More impor-
tantly, the hybrid metal nanoplatform (HMCuS/[email protected]) allowed several emerging exceptional
characteristics. Our studies have substantiated the hybrid nanoparticles possessed an enhanced PTT
effect due to coupled plasmonic resonances with an elevated heat-generating capacity. Notably, an effec-
tive removal of IONP-caps occurred after NIR-induced photo-hyperthermia via weakening of the coordi-
nation interactions between HMCuS-NH2 and IONPs, which suggested the feasibility of sophisticated
controlled on-demand drug release upon exposing to NIR stimulus with spatial/temporal resolution.
Benefiting from the favorable magnetic tumor targeting efficacy, the in vitro and in vivo experiments indi-
cated a remarkable anti-tumor therapeutic efficacy under NIR irradiation, resulting from the synergistic
combination of chemo-phototherapy. In addition, T2-weighted magnetic resonance imaging (MRI) con-
trast performance of IONPs provided the identifica.
This document presents a synopsis for a study on the development of a brucine transdermal drug delivery system using micro-needle assisted transinvasomal gel for the treatment of arthritis. The objectives are to develop brucine invasomes to increase skin penetration and systemic distribution for improved transdermal administration and bioavailability. Some pre-formulation studies including drug characterization and analytical method development have been completed. Remaining work includes invasome formulation/optimization, characterization, stability testing, and evaluation of anti-arthritic activity. The synopsis was submitted in partial fulfillment of an M.Pharm degree in quality assurance.
This document summarizes the role of clinical pharmacists in diagnostic imaging procedures that utilize contrast agents or radiopharmaceuticals. It discusses how clinical pharmacists are experts in drug management and can help ensure proper use and monitoring of contrast agents and radiopharmaceuticals. The document also reviews literature showing that involvement of clinical pharmacists in imaging procedures can improve patient outcomes and safety while reducing costs.
High-throughput screening (HTS) is a scientific method used in drug discovery that allows researchers to quickly test millions of chemical, genetic, or pharmacological compounds using robotics, detectors, and other automated tools. The key tool is a microtiter plate containing hundreds to thousands of wells, each with a different compound. Automated systems transfer plates between stations for mixing, incubation, and analysis to generate large amounts of experimental data. Effective experimental design, quality control, and data analysis methods are needed to identify meaningful results, or "hits", from large HTS datasets. Recent advances allow screening millions of reactions much faster and with less reagent volume than before.
The document discusses stability testing of pharmaceutical products. It defines the purpose of stability testing as providing evidence of how a product's quality varies over time under the influence of factors like temperature, humidity and light. There are two main types of stability studies: stability studies and accelerated stability studies. Stability studies involve testing products under various storage conditions like long term, intermediate and accelerated conditions over minimum time periods to establish a product's shelf life.
1. Research paper
Terahertz study on porosity and mass fraction of active pharmaceutical
ingredient of pharmaceutical tablets
Prince Bawuah a,⇑
, Nicholas Tan b
, Samuel Nana A. Tweneboah a
, Tuomas Ervasti c
, J. Axel Zeitler b
,
Jarkko Ketolainen c
, Kai-Erik Peiponen a
a
Institute of Photonics, University of Eastern Finland, P.O. Box 111, FI-80101 Joensuu, Finland
b
Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge CB2 3RA, United Kingdom
c
School of Pharmacy, Promis Centre, University of Eastern Finland, P.O. Box 1617, FI-70211 Kuopio, Finland
a r t i c l e i n f o
Article history:
Received 7 March 2016
Revised 4 May 2016
Accepted in revised form 7 June 2016
Available online 8 June 2016
Keywords:
Pharmaceutical tablet
Microcrystalline cellulose
Active pharmaceutical ingredient
Porosity
Terahertz
Effective refractive index
Effective absorption coefficient
Strain
a b s t r a c t
In this study, terahertz time-domain spectroscopic (THz-TDS) technique has been used to ascertain the
change in the optical properties, as a function of changing porosity and mass fraction of active pharma-
ceutical ingredient (API), of training sets of pharmaceutical tablets. Four training sets of pharmaceutical
tablets were compressed with microcrystalline cellulose (MCC) excipient and indomethacin API by
varying either the porosity, height, and API mass fraction or all three tablet parameters.
It was observed, as far as we know, for the first time, that the THz time-domain and frequency-domain
effective refractive index, as well as, the frequency-domain effective absorption coefficient both show
linear correlations with the porosity and API mass fraction for training sets of real pharmaceutical tablets.
We suggest that, the observed linear correlations can be useful in basic research and quality inspection of
pharmaceutical tablets.
Additionally, we propose a novel optical strain parameter, based on THz measurement, which yields
information on the conventional strain parameter of a tablet as well as on the change of fill fraction of
solid material during compression of porous pharmaceutical tablets.
We suggest that the THz measurement and proposed method of data analysis, in addition to providing
an efficient tool for basic research of porous media, can serve as one of the novel quality by design (QbD)
implementation techniques to predict critical quality attributes (CQA) such as porosity, API mass fraction
and strain of flat-faced pharmaceutical tablets before production.
Ó 2016 Elsevier B.V. All rights reserved.
1. Introduction
Pharmaceutical solid dosage forms (tablets) are among the most
widely administered pharmaceutical products due to the ease of
large-scale production, stability and efficient means of drug intake
by patients. Even though much effort has been devoted to improv-
ing the efficacy and safety of pharmaceutical tablets, yet pharma-
cists are interested in search of fast and non-destructive methods
and techniques to optimize the quality and efficacy of all pharma-
ceutical tablets before reaching the end-users. To achieve this
demand, and bearing in mind the number of tablets produced
per hour in pharmaceutical industries, pharmacists have recently
resorted to the use of optical techniques [1–4]. This is due to the
fact that optical methods can meet the desired measuring speed,
for example in THz sensing [5]; that is, in principle, it is capable
of checking each tablet in the production line. As far as we know,
there is no in-process control for the detection of porosity during
tablet production, and off-line detection of porosity is typically
based on the use of commercial mercury porosimeters. Unfortu-
nately, commercial mercury porosimeters utilize destructive mea-
surement method. Hence, in the frame of process analytical
technology (PAT), there is a desire to have non-destructive
methods of measurement of porosity and also other important
properties of pharmaceutical tablets. For the purpose of visual
inspection of pharmaceutical tablets, several imaging techniques
have been employed, especially for the quality assessment of
imprint on tablet [6] and coating properties [7,8] of tablets.
Nonetheless, some of these optical techniques can be somewhat
destructive, especially due to the use of high power laser for tablet
inspection. For example, focusing of a laser beam over a pharma-
ceutical tablet can cause photo-bleaching, and therefore photo-
chemical changes of the tablet during optical inspection. The
quest to achieve both speed and non-destructive measurements
http://dx.doi.org/10.1016/j.ejpb.2016.06.007
0939-6411/Ó 2016 Elsevier B.V. All rights reserved.
⇑ Corresponding author.
E-mail address: prince.bawuah@uef.fi (P. Bawuah).
European Journal of Pharmaceutics and Biopharmaceutics 105 (2016) 122–133
Contents lists available at ScienceDirect
European Journal of Pharmaceutics and Biopharmaceutics
journal homepage: www.elsevier.com/locate/ejpb
2. has recently triggered the use of THz-TDS technique for the assess-
ment of various properties of pharmaceutical tablets [9–11]. THz
radiation has relatively long wavelength and low energy (i.e. no
ionization of sample) that can interact with optical phonons in
their different crystal lattices [12,13]. This unique property of
THz radiation has been used for the identification of different poly-
morphs of some major pharmaceutical ingredients [14,15] based
on their intrinsic spectral fingerprints at THz frequencies. In a
recent review, THz-TDS has been used to study the crystallization
of amorphous drugs by monitoring the onset and strength of the
molecular mobility [16].
Porous media such as pharmaceutical tablets contain inclusions
(inhomogeneities) whose dimensions (ca. 1–100 lm) are relatively
small compared to the wavelength of a given THz wave (100–
3000 lm). The relatively small dimensions of these inclusions
compared to the THz wavelength result in no or low scattering of
the incident THz radiation. This condition has permitted the use
of effective medium theories such as Maxwell Garnett [17],
Bruggeman [18], Wiener bounds [19], and Hashin-Shtrikman
bounds [20] to predict the effective properties of bulk pharmaceu-
tical tablets including the intrinsic properties of the individual
inclusions in the tablet in the THz range of the electromagnetic
spectrum. The effective medium theories provide a link between
the microscopic and macroscopic properties of porous media.
A useful property, which forms the central objective of this
study is that, with THz-TDS, one can easily obtain the optical
constants such as refractive index and absorption coefficient of
pharmaceutical tablets via either the time-domain or frequency-
domain signal processing techniques. Usually, the extracted optical
constants are considered as effective properties due to the compo-
sition of a pharmaceutical tablet, i.e. excipient(s), API and air voids.
The knowledge of the optical constants can serve as the back-
bone for further extraction of other quality parameters such as
weight, height, porosity and the intrinsic properties of the various
inclusions of the tablet’s matrix using non-contact THz measure-
ment technique [18,21]. From these quality parameters, one could
further predict important tablet properties such as dissolution, fri-
ability, API mass fraction and tensile strength [22]. Due to the
inevitable dependence of the quality parameters of a given phar-
maceutical tablet on its optical constants, our previous work has
been devoted to finding the correlation between the effective
refractive index and parameters such as porosity and surface
roughness of training sets of pharmaceutical compacts composed
of MCC only [18]. However, a reliable generalization of our previ-
ous observations requires a more detailed assessment with real
pharmaceutical tablets. By real pharmaceutical tablet, we mean a
tablet that contains API in a solid matrix (excipient). This study
utilizes four different training sets of pharmaceutical tablets that
contain MCC (here we use different grades from that used in
[18]) as the excipient and indomethacin as an API. With these sets
of tablets, an important question arises whether a linear correla-
tion previously observed between the effective refractive index
and the porosity of tablets without API [18] is valid for tablets with
API. The answer is yes as will be shown in this article. Similarly, we
show, as far as we know, for the first time, a linear correlation
between the THz effective refractive index and the API mass frac-
tion of real pharmaceutical tablets instead of typical pellets used
in THz-TDS measurements. Furthermore, analysis was carried out
to quantify, compare and contrast the magnitude of change on
both the time-domain and frequency-domain refractive index by
varying either porosity only and API mass fraction only or both
parameters in the training sets of the pharmaceutical tablets. Lin-
ear correlation between tablet’s properties and optical constants,
such as effective refractive index and effective absorption coeffi-
cient, is demonstrated to hold also in the frequency-domain.
In the realms of QbD [23], porosity is considered as one of the
CQA due to its direct effect on the dissolution rate and friability
of a pharmaceutical tablet. Hence, several studies have been con-
ducted to characterize pharmaceutical compacts using different
methods, e.g. depolarization metrics of laser light scattering [24].
Due to the observed linear correlation between effective refractive
index, porosity and API mass fraction of the training tablet sets, the
present study introduces and demonstrates a three-dimensional
(3D) plane concept that can serve as a visual aid to understand
how the three parameters namely effective refractive index,
porosity and API mass fraction depend on each other. Finally, the
findings of this study can serve as a process analytical technology
(PAT) tool to predict CQA such as porosity and API mass fraction
during the design of experiment (DoE), which is an important
element in QbD in the development of new product or the
optimization of existing ones.
2. Theory
In the context of a porous pharmaceutical tablet the refractive
index of the tablet is termed ‘‘effective” due to the various compo-
sitions of the pharmaceutical tablet such as air, excipients and API.
If H and Dt are the height and the measured THz pulse time
delay of the tablets respectively, the effective refractive index neff
can be obtained from the expression of optical path length as
follows,
ðneff ðfÞ À 1ÞH ¼ cDt; ð1Þ
where c is the speed of light in vacuum, f is the porosity of the tablet
and the assumption made is that, the effective refractive index has
the same value all over the tablet. The reference in the measure-
ment is typically air or nitrogen gas, and the refractive index of
the reference is assumed to be equal to one.
A linear relationship was observed between neff and a discrete
set of porosity values for pharmaceutical compacts containing
MCC only in our previous study as follows [18]:
neff ðfÞ ¼ nð0Þ þ ð1 À nð0ÞÞf; ð2Þ
where n(0) is a fitting parameter, namely the zero porosity estimate
of refractive index of MCC. The numerical value of n(0) is applicable
for data analysis by Eq. (2) at least inside the porosity range of mea-
surements where the linear relationship is valid. The present study
aims at ascertaining the effect of the combination of both porosity
and API mass fraction (x) on the effective refractive index of training
sets of real pharmaceutical tablets. These sets consisted of MCC
with refractive index of nMCC and API (indomethacin) with refrac-
tive index as nAPI. In order to graphically illustrate the linear depen-
dency of the effective refractive index on both the porosity and API
mass fraction, we imagine a triangle of vertices P1 (1,0,1), P2 (0,0,
nMCC), P3 (0,1,nAPI) drawn in the Cartesian coordinate system (f,x,
neff) (see Fig. 1). The chosen vertices of the triangle correspond to
reality since one would expect to have the effective refractive index
to be equal to that of air if the porosity of a tablet is 100% as
depicted by point P1. Point 2, P2, physically means that, at zero
porosity and zero API mass fraction, the effective refractive index
of the tablet is equal to the refractive index of MCC, nMCC, since
the composition of the tablet tends to be MCC only. Finally, P3
depicts a tablet made of API only since the API mass fraction is
100 wt% without any air voids (refractive index of API is nAPI). In
the simulation of Fig. 1, we have assumed that nMCC > nAPI. Natu-
rally, cases with greater refractive index of API than those of excip-
ient are possible. From the vertices of the triangle in Fig. 1, and by
utilizing the principles of analytic geometry [25], we derived the
equation of a plane as
P. Bawuah et al. / European Journal of Pharmaceutics and Biopharmaceutics 105 (2016) 122–133 123
3. neff ðf; xÞ ¼ nMCC À ðnMCC À 1Þf À ðnMCC À nAPIÞx; ð3Þ
where f and x are independent variables (the mass fraction of the
MCC is given by 1 À x). The validity of Eq. (3) will be shown for
the case of the four training tablet sets in this study. In reality,
the combination of values of f and x is restricted between (0,0) 6
(f,x) 6 (1,1), which is a rectangular unit area in the (f,x) - plane.
Obviously, Eq. (3) describes, instead of the full space of an infinite
tilted plane, a triangle, which is a ‘‘sub-space” of the infinite plane.
Practically speaking, the values of f, x and neff of real pharmaceutical
tablets usually occupy a relatively small local area in the graphical
description of the plane defined by Eq. (3). In order to test the
validity of Eq. (3), this study presents experimental data of real
pharmaceutical tablets with varying porosity and API mass fraction.
We show that all the obtained refractive index data will follow the
law of Eq. (3), and hence lie on the plane illustrated in Fig. 1.
Furthermore, a comparative analysis on the magnitude of the
changes in the neff due to changing only the porosity and only
the API mass fraction was conducted. From Eq. (3), one can write
the change of the effective refractive due to changing only the
porosity, Dneff (f), as
Dneff ðfÞ ¼ ÀðnMCC À 1ÞDf; ð4Þ
whereas in the case of the change of API mass fraction only, Dneff
(x), is given by
Dneff ðxÞ ¼ ÀðnMCC À nAPIÞDx; ð5Þ
where Df and Dx are the change in porosity and API mass fraction,
respectively.
Mechanical properties of pharmaceutical tablets have much
importance. Herein, we present theory for a novel concept that is
closely related to the true strain of pharmaceutical tablets in the
realms of THz time-delay measurement techniques. This approach
can serve as a novel technique for the inspection of the mechanical
properties of pharmaceutical tablets. The true ‘‘mechanical” strain
(emech) of a medium is defined by the integral
emech ¼
Z H
H0
dH
H
¼ ln
H
H0
; ð6Þ
where H0 is the initial height of the medium and H is the reduced
height after compression of the medium. In a similar analogy, we
can define an ‘‘optical” strain (eopt) using the concept of optical path
length of the porous tablet, namely
eopt ¼
Z neff H
neff;0H0
dðneff HÞ
neff H
¼ ln
neff H
neff;0H0
¼ ln
neff
neff;0
þ ln
H
H0
¼ ln
neff
neff;0
þ emech; ð7Þ
where neff,0 is the effective refractive index of a tablet with initial
height H0 and the property of logarithm, ln(AB) = lnA + lnB, was
used.
It is obvious from the definition given in Eq. (7) that it is possi-
ble to separate mechanical strain and the contribution due to the
refractive index of the medium. Eq. (7) holds, generally, for any
optical technique in the absence of light scattering. However, in a
case similar to this study, where the time-delay (calculated based
on the time-of-flight difference between reference THz pulse and
sample THz pulse) is known, a practical definition of the optical
strain based on the utilization of the optical path length defined
by Eq. (1) should be derived. Hence, we redefine the optical strain
in terms of THz pulse delay measurement (eTHz) as follows:
eTHz ¼
Z ðneff À1ÞH
ðneff;0À1ÞH0
dððneff À 1ÞHÞ
ðneff À 1ÞH
¼ ln
ðneff À 1ÞH
ðneff;0 À 1ÞH0
¼ ln
neff À 1
neff;0 À 1
þ ln
H
H0
¼ ln
neff À 1
neff;0 À 1
þ emech: ð8Þ
Now, the logarithm given in the second equality in Eq. (8)
can be expressed in terms of the THz pulse time delay data
(see Eq. (1)), namely
eTHz ¼ ln
Dt
Dt0
¼ ln
neff À 1
neff;0 À 1
þ emech: ð9Þ
Next we utilize the linear relation between the effective
refractive index and porosity given in Eq. (2) and substitute this
expression of neff (f) into Eq. (9). Hence, after some algebra we
get an expression
eTHz ¼ ln
Dt
Dt0
¼ ln
1 À f
1 À f0
þ emech: ð10Þ
This is rather interesting expression because the first logarithm
in Eq. (10) is obtained by time delay measurement of a pulse of
electromagnetic radiation only, whereas the two expressions on
the right hand-side of the second equality in Eq. (10) describe
purely material and mechanical properties of the tablet. Note that
1 À f0 and 1 À f are the fill fractions of the solid medium of the
tablet before and after compression, and the change of the porosity
of the tablet is equal to Df = f0 À f. Evidently the optical strain is a
more general concept than the pure mechanical strain because, in
addition to containing information on the conventional true strain,
it also gives information on the relative change of the fill fraction of
the solid medium (ratio of fill fractions) due to compression and
hence reduction in the tablet height. This logarithmic ratio of fill
fraction can serve as a new useful quality parameter of pharmaceu-
tical tablets.
3. Materials and methods
3.1. Materials
Four sets of flat-faced pharmaceutical tablets with 13 mm
diameter were compacted from microcrystalline cellulose, MCC
(Avicell PH101, FMC BioPolymer, Philadelphia, USA) as the excipi-
ent with indomethacin (Hangzhou Dayangchem Co. Ltd, Hangzhou,
China) as the active pharmaceutical ingredient (API). These sam-
ples were used as received. The MCC grade, Avicell PH101, has a
nominal particle size of 50 lm and a true density of 1.56 g cmÀ3
whereas the indomethacin (mostly used as a painkiller), in its
Fig. 1. A simulated plane showing the relationship between the effective refractive
index, porosity and API mass fraction of pharmaceutical tablets. The points P1, P2
and P3 used in the derivation of Eq. (2) are shown as nair, nMCC, and nAPI respectively.
The black portions (marks) in the plane show the occupied locations of the training
sets of pharmaceutical tablets used in the study.
124 P. Bawuah et al. / European Journal of Pharmaceutics and Biopharmaceutics 105 (2016) 122–133
4. crystalline gamma polymorph has a true density of 1.37 g cmÀ3
.
The choice of MCC, apart from being a conventional pharmaceuti-
cal excipient, is based on the fact that MCC is a good disintegrant, a
filler and can be directly compacted at low pressure [26]. Due
to these merits, MCC has been an interesting object of study
using THz measurement techniques [27]. On the other hand,
molecular understanding of compressibility and resulting porosity
of c-polymorph of indomethacin have been studied in [28].
3.2. Tablet compaction
All the sets were compacted with a compaction simulator
(PuuMan Ltd, Kuopio, Finland) and the detailed tableting process
has been described previously in [29]. With a compaction simula-
tor, pharmacists have the possibility to adjust and control the
values of the compaction parameters such as porosity and height
of the tablet during the compression processing. Other advantages
of the compaction simulator include the following: the ability to
choose different compression cycles of lower and upper punches
and adjust the magnitude of the compression force. The porosity
and height properties of the tablets were changed by changing
the total mass of the MCC and indomethacin powders (see Tables
1 and 2) used during compaction.
In sets 1 and 2, the porosity and height were varied respectively,
but the API mass fraction in both sets was kept constant at ca.
10 wt%. Set 3 composed of tablets with varying API mass fraction
but constant porosity. In set 4, all the parameters (i.e. porosity,
height and API mass fraction) were varied. Both sets 1 and 3 tablets
had nominally constant value of height of $3 mm whereas for the
sets 2 and 3, the porosity was kept at a nominally constant value of
ca. 36%.
3.3. Tablet porosity
The density of each pharmaceutical tablet was calculated from
their dimensions (i.e. height and diameter) and weight. The dimen-
sions of the tablets were measured a day after compaction to avoid
measurement errors due to possible mechanical relaxation of the
tablets. The tablet dimensions were measured with a micrometer
(Digitrix, NSK, Japan) whereas an analytical balance (Mettler
Toledo AG245, Schwerzenbach, Switzerland) was used for the
weight measurement. The true densities of MCC (1.5573 g cmÀ3
)
and indomethacin (1.3701 g cmÀ3
), given by the manufacturers,
were used in the calculation of the porosities of the tablets.
It is worth noting that, for a given sample number (Table 1), five
pharmaceutical tablets were compressed. Hence, we present the
measured average values of the varying parameters for all tablets
in each set (Table 1). The total number of pharmaceutical tablets
used for the THz measurements was 110 tablets.
For each tablet sets, errors in the calculations made for
the nominal porosities are as follows: diameter ± 0.008 mm,
height ± 0.005 mm (standard deviation of the sample mean),
weight ± 0.01 mg (readability of the scale) and porosity ± 0.2%
(calculated using the error propagation law).
3.4. THz time-domain measurements
The terahertz pulse time delay of these sets was measured using
a THz-TDS with setup similar to that described previously [30,31].
The simplest case is when the effective refractive index is retrieved
from the THz pulse time delay that is calculated from the measured
time difference between the sample and reference pulses
(see Eq. (1)).
3.5. Frequency-domain analysis of time-domain THz measurement
data
Apart from the straightforward time-domain measurement
described above, we have also estimated the frequency-
dependent optical constants of the training sets of pharmaceutical
tablets. Accurate extraction of the frequency dependent optical
constants such as the effective refractive index and the effective
absorption coefficient in THz transmission measurement is based
on the measurement of the electric field amplitude of both the
sample and the reference signal in time-domain. These acquired
time-domain waveforms are converted to the frequency domain
via fast Fourier transform (FFT) before further processing. Normal-
izing the sample spectrum by the reference spectrum yields the
complex-valued transmission function from which both the fre-
quency dependent effective refractive index, neff, and the effective
absorption coefficient, aeff, are extracted. Readers interested in the
description of the data analysis, parameter retrieval processes and
the working principles of the THz-TDS are referred to [32–35].
In a similar manner as described in the time-domain analysis
below, the change of both the frequency-dependent effective
absorption coefficient and effective refractive index as a result of
changing porosity and API mass fraction is discussed in the next
section. Finally, we have investigated the correlation between the
change in the effective absorption coefficients at a given frequency
and the change in both porosity and API mass fraction of the train-
ing sets of pharmaceutical tablets.
4. Results and discussions
4.1. THz time-domain analysis
The measured pulse delay was used to estimate the effective
refractive index for the various sets of tablets using Eq. (1). This
straightforward refractive index extraction technique, as discussed
previously, is relatively fast and, in principle, capable of meeting
the measurement speed needed for an inline tablet inspection.
The measurement error of the effective refractive index is ca.
±0.002 [29]. The effective refractive index, under this contest, is
considered to be given at a virtual frequency since the THz pulses,
from which the refractive indices were extracted, are composed of
a broad band of THz frequencies.
The values recorded for both the Dt and neff for the different
sets, and even for tablets within the same set (see Table 5) varied,
as expected, due to the different compaction parameters used
Table 1
Data of tablet set 1. The mean values of the diameter d, height H, weight W, density q,
and porosity f. The API mass fraction and height are kept at a constant value of 10 wt%
and 3 mm, respectively.
Sample number d (mm) H (mm) W (mg) q (g cmÀ3
) f (%) x (wt%)
1 13.123 3.031 342.49 1.54 46 10
2 13.113 3.033 356.90 1.54 43 10
3 13.120 3.018 370.92 1.54 41 10
4 13.106 3.013 385.17 1.54 38 10
5 13.110 3.007 400.10 1.54 36 10
Table 2
Data of tablet set 2. The mean values of the diameter d, height H, weight W, density q,
and porosity f. The API mass fraction and porosity are kept at a constant value of
10 wt% and 36% respectively.
Sample number d (mm) H (mm) W (mg) q (g cmÀ3
) f (%) x (wt%)
1 13.097 2.742 361.47 1.539 36 10
2 13.078 3.333 438.73 1.539 36 10
3 13.066 3.626 476.45 1.539 36 10
4 13.062 3.927 514.70 1.539 36 10
P. Bawuah et al. / European Journal of Pharmaceutics and Biopharmaceutics 105 (2016) 122–133 125
5. during the tableting process. Comparatively, these new sets seem
to have higher values of neff than the sets of our previous studies
[18]. This observed difference in magnitude of the effective refrac-
tive indices is most probably due to the use of different MCC grades
and the presence of the API in these new sets 1–4.
In order to investigate the effect of porosity and API mass
fraction on the effective refractive index, we have utilized Eqs.
(4) and (5). In these equations one has to know the zero-porosity
refractive indices of MCC and API. These are obtained by an extrap-
olation process similar to that suggested in [21]. In Fig. 2, set 3
tablet samples with varying API mass fraction were utilized. By
extrapolating the API mass fraction within the range of 0–100 wt
%, the refractive indices of MCC only and that of API only at 36%
porosity were obtained (see Fig. 2(a)). The obtained refractive
index values at 36% in addition to the choice of an anchor point
namely (n = 1 at f = 100%) were used in the linear extrapolation
(Fig. 2(b)) to determine the estimates of the zero-porosity refrac-
tive index of both MCC and API, i.e. nMCC = 1.85, nAPI = 1.61. These
‘‘intrinsic” refractive index values were used only for an illustrative
purpose (Fig. 1) and also for theoretical estimation of effective
refractive index change of a tablet that is due to porosity or API
mass fraction change only, as will be demonstrated below.
An experimental clue of how the effective refractive index
varies as a function of both the porosity and the API mass fraction
given by Eq. (3) has been illustrated (Fig. 3). In Fig. 3, we have plot-
ted data points of all the tablets used under each sample number
(see Tables 1–5) for sets 1–4 samples without taking their average.
The linear relation observed between neff and f, for example, of sets
1 and 4 further proves the validity of Eq. (3). Apart from proving
the validity of Eq. (3), we show for the first time that, even for
three-phase (i.e. air-MCC-API) pharmaceutical tablets, a linear rela-
tion still exists between the effective refractive index and the
porosity range we are dealing with.
It is interesting to get theoretical but quantitative estimates for
the effective refractive index change regarding the change of
porosity only and API mass fraction only. By substituting the value
of 0.1 for the change in the porosity (i.e. set 1) and 0.15 as the
change in the API mass fraction (i.e. set 3) into Eqs. (4) and (5)
respectively, we obtained 0.085 as the recorded change in the
effective refractive index due to the change in porosity only and
0.036 as the recorded change due to changing only the API mass
fraction. This shows that changing the porosity induces higher
change in the effective refractive index than changing the API mass
fraction. A close manifestation of this observation is shown in the
experimental data of sets 1 and 3 (Fig. 3(a) and (c)). Thus, a com-
parison made between Df (i.e. 10%) and Dx (i.e. 15%) of sets 1
and 3 to their respective experimental change in the effective
refractive index (i.e. Dneff (f) = 0.083, Dneff (x) = 0.022) has further
strengthened the validity of the calculated change of the effective
refractive index value obtained from Eqs. (4) and (5) above.
Furthermore, by bearing in mind the narrow change in the API
mass fraction in set 4, and considering Figs. 3(a) and 3(d), we infer
that doubling Df approximately doubles Dn.
Moreover, the change in the effective refractive index values of
set 2 samples (Fig. 3(b)) shows that varying only the height of a
tablet, as expected, has no significant effect on the neff (therefore
in the latter part of this study we do not present data for the set
2 anymore). By this observation, it is valid to attribute the change
observed in the effective refractive index of the set 4 (i.e. where all
the parameters are being varied) to only two varying parameters,
namely porosity and API mass fraction. Hence in the discussion
below we present data for sets 1, 3 and 4 only. But before that
we briefly deal with the concept of the height of pharmaceutical
tablets.
Building on the issue concerning the variations in the height of
pharmaceutical tablets, we next briefly demonstrate the use of THz
time-delay measurement for checking the presence of an unac-
ceptable height variation of tablets, which can inform pharmacists
the possible mechanical relaxation of pharmaceutical tablets after
compaction. The presence of possible height change due to
mechanical relaxation of pharmaceutical tablets can alter the
porosity of such tablets. Hence, this study seeks to ascertain and
to demonstrate how the porosity variations of tablets can be mon-
itored in cases where the height of the pharmaceutical tablets falls
within the optimum/acceptable range. By this demonstration, we
have assumed that the set 2 (see Table 2) presents tablets with a
Fig. 2. An illustration of the use of the linear extrapolation technique in the estimation of the zero-porosity refractive indices of MCC, nMCC (0%) and API, nAPI (0%). Set 3
samples with varying API mass fraction were used for the analysis. (a) Illustrates a linear extrapolation of the effective refractive index in terms of the API mass fraction
whereas (b) shows similar extrapolation in terms of the porosity.
126 P. Bawuah et al. / European Journal of Pharmaceutics and Biopharmaceutics 105 (2016) 122–133
6. targeted constant porosity and API mass fraction but with thick-
nesses that are subject to abnormal change. Since the effective
refractive index of the tablets is a constant in such a case, the time
delay of the THz depends on the height of the tablet. This is evident
from Eq. (1) because Eq. (1) presents a straight line as a function of
H. It is evident from Eq. (1) that at H = 0, Dt = 0, hence the line goes
via the origin (Fig. 4). The slope of the line provides information on
the effective refractive index (set 2 in this case) for the given poros-
ity. Using the data of set 2 samples (Fig. 4), we got an estimate for
the effective refractive index of neff = 1.536 from the slope of the
fitted line. This value matches quite well with the effective refrac-
tive index of set 2 samples (Table 5). Thus, by keeping both the f
and x constant and varying only the height, we can get information
about the effective refractive index of the tablet. This is interesting
since pharmacists may set an optimal height for a batch of tablets
and hence we can use this idea to get any variation of THz pulse
delay which is due to variation of f of such batch of tablets or vice
versa. To buttress this argument, we utilize the data of tablet set 1
Fig. 3. Comparison of the effect of porosity and API mass fraction on the effective refractive index for (a) set 1, (b) set 2, (c) set 3 and (d) set 4. Dneff, Df, Dx and DH give the
differences between maximum and minimum values for the change in the effective refractive index, porosity, API mass fraction and height respectively. The values of the
slope, s, for sets 1 and 4 are given.
Table 3
Data of tablet set 3. The mean values of the diameter d, height H, weight W, density q,
porosity f, and API mass fraction x. The porosity and height are kept at a constant
value of 36% and 3 mm, respectively.
Sample number d (mm) H (mm) W (mg) q (g cmÀ3
) f (%) x (wt%)
1 13.104 3.034 410.55 1.557 36 0.00
2 13.079 3.023 403.13 1.550 36 3.75
3 13.103 3.025 403.04 1.543 36 7.50
4 13.100 3.001 401.90 1.541 36 8.75
5 13.097 3.016 401.15 1.539 36 10.00
6 13.099 3.036 400.56 1.536 36 11.25
7 13.096 3.034 399.82 1.534 36 12.50
8 13.110 3.039 400.20 1.529 36 15.00
Table 4
Data of tablet set 4. The values of the diameter d, height H, weight W, density q,
porosity f, and API mass fraction x.
Sample number d (mm) H (mm) W (mg) q (g cmÀ3
) f (%) x (wt%)
1 13.081 2.738 405.86 1.54 28 9.0
2 13.090 2.960 405.44 1.54 34 9.5
3 13.093 3.279 405.92 1.54 40 10.0
4 13.083 3.654 403.45 1.54 47 10.5
5 13.081 3.947 403.56 1.54 50 11.0
Table 5
The calculated pulse delay (Dt) and the effective refractive index (neff) of the four sets
of pharmaceutical tablets. The absolute measurement error of effective refractive
index is ca. ±0.002 and the porosity ca. ±0.5% [29].
Sample
number
Set 1 Set 2 Set 3 Set 4
Dt
(ps)
neff Dt
(ps)
neff Dt
(ps)
neff Dt
(ps)
neff
1 4.551 1.444 4.850 1.529 5.589 1.543 5.535 1.602
2 4.780 1.464 5.948 1.533 5.497 1.537 5.480 1.551
3 4.959 1.484 6.491 1.536 5.442 1.527 5.470 1.498
4 5.160 1.506 7.023 1.535 5.437 1.529 5.404 1.441
5 5.345 1.527 5.437 1.526 5.372 1.405
6 5.426 1.524
7 5.415 1.522
8 5.372 1.521
P. Bawuah et al. / European Journal of Pharmaceutics and Biopharmaceutics 105 (2016) 122–133 127
7. and simulate by setting for a tablet, an optimal height of 3 mm,
porosity of 0.36 and API mass fraction of 10 wt%, respectively.
We then compared the optical path length of tablets with the
optimal optical path length cDt (Fig. 4).
To throw more light on how the change of porosity affects the
effective refractive index, a linear correlation, with an average
slope, s, of 0.0089, was observed between the change in the
effective refractive index and the change in porosity for both sets
1 and 4 samples (see Fig. 5). It is clearly seen that even at narrow
intervals of porosity change, the linear relationship between poros-
ity and effective refractive index still seems to be valid. This obser-
vation is true for flat-faced tablets as well as tablets containing
either fixed or varying amount of API (Fig. 5).
Furthermore, a linear correlation was observed between the neff
and the x (Fig. 6). This observation further proves, at least, a local
validity of Eq. (3) in the Cartesian 3D system.
Although this linear observation between neff and f (see Fig. 3
(a) and (d)) is quite promising, it was demonstrated in the present
study to be applicable to flat-faced tablets. Since most pharmaceu-
tical tablets have curved surfaces, there is a need for further inves-
tigations on curved surface samples containing API using a concept
similar to the training sets 1–4 of this study. This requires more
theoretical and experimental investigations and will be the moti-
vation for our future studies.
Finally, the black portions (marks) on the tilted plane (Fig. 1)
give a visual demonstration of the correlation between the effec-
tive refractive index, porosity and API mass fraction of the four
training sets of pharmaceutical tablets. Also for a given range of
porosity and API mass fraction for pharmaceutical tablets and
using Fig. 1, one can envisage a rectangle on the f, x plane that
can be projected on the 3D plane to predict the range of the effec-
tive refractive index as well. This concept of 3D plane could also
serve as a quick visual quality inspection aid to monitor the history
of the properties of batches of pharmaceutical tablets produced
over time.
4.2. THz frequency-domain analysis
Building on the frequency domain analysis, we have retrieved
both the frequency dependent effective absorption coefficient (aeff)
and the effective refractive index, of sets 1–4 samples and have
compared the magnitude of variation of these optical constants
due to the change in the porosity and API mass fraction. The ampli-
tude data utilized for the data analysis were obtained by scanning
both the sample and reference THz electric field through proper
adjustment of the delay line during the measurement. Fast Fourier
transform (FFT) technique was employed to convert the time-
domain amplitude signal into frequency-domain. From the
complex-valued frequency dependent transmittance coefficient,
it is possible to extract information on effective refractive index
and effective absorption coefficient of the pharmaceutical tablet.
Although the scanning of the THz pulse to detect the amplitude
is time-consuming compared to the time-domain analysis dis-
cussed above, modern advancement in detector technology has
made it possible to measure high-quality terahertz spectra in less
than 20 ms [5].
Similar analysis performed as in the case of the neff (Fig. 3),
reveals from Fig. 7 that the increment in both the porosity and
API mass fraction causes a decrease in the frequency dependent
effective absorption coefficient of sets 1, 3 and 4 (see Fig. 7(a), (c)
and (e)) samples. As an example, we plotted the magnitude of
the change in the effective absorption coefficient (Daeff) at 0.8
THz of sets 1 and 3 due to changing porosity only (Fig. 7(a)), and
API mass fraction only (Fig. 7(c)). Based on the calculated values
of Daeff (Fig. 7(a), (c) and (e)), it is obvious that the combined effect
of both porosity and API mass fraction on the change in the effec-
tive absorption coefficient can be relatively strong especially at
higher frequencies but we will take a closer look at this property
a bit later.
For the change in frequency-dependent effective refractive
index (Dneff), which is due to the change of porosity and API mass
fraction of sets 1, 3 and 4 (Fig. 7(b), (d) and (f)), the observations
made are akin to that of neff (Fig. 3). Even the recorded Dneff values
at 0.8 THz closely match with their counterparts in Fig. 3. Obvi-
ously the effective refractive index curves (Fig. 7) show a
plateau-like behavior at 0–1.5 THz, which suggests no or low dis-
persion of the THz wave. Dispersion, when present, plays an
important role regarding the THz pulse position since it broadens
and thus, causes re-shaping of the THz pulse. Relatively strong dis-
persion is accompanied with relatively high absorption [36]. In
such a case, detecting a THz transmission signal from 3 mm thick
sample is usually problematic.
Next we pay attention to the spectral interpretation of the
absorption data. It is interesting to observe from the absorption
coefficient curves (Fig. 7) the absence of the spectral fingerprints
Fig. 4. Variation of cDt as a function of H for set 2 tablets. The solid line (calibration
line with slope s) has been fitted to four data points, and the fifth point in origin
comes from the theory. The dashed horizontal and vertical lines indicate the
optimal tablet height and THz time delay. The value of 3 mm is used as an optimal
tablet height. Points (b)–(d) present data for the tablet set 1 which deviate from the
optimum operation point due to variation of porosity of the tablet. Point (a) is close
to the optimum point.
Fig. 5. An illustration of the correlation between the change in the refractive index
and the change in porosity for sets 1 and 4 samples.
128 P. Bawuah et al. / European Journal of Pharmaceutics and Biopharmaceutics 105 (2016) 122–133
8. of c-crystalline form of indomethacin despite its reported finger-
prints at 1.2, 1.5 and 2.0 THz [37,38] for powder substance. This
might be due to the possible phase change of the API from
crystalline to amorphous phase during the tablet compression
but more probable reason is the relatively low API mass fractions
of these training sets compared to the API mass fractions used in
[37,38]. Anyhow, it is obvious from Fig. 7(a), (c) and (e) that there
are actually three things that have an effect on the absolute mag-
nitude of the effective absorption coefficient, namely porosity
and API plus MCC mass fractions of a tablet. In the case of Fig. 7
(a) the API mass fraction is fixed but the porosity is a variable.
Obviously, an increase in porosity decreases the frequency-
dependent effective absorption coefficient (Fig. 7(a)). In the case
of set 3 samples (Fig. 7(c)), the porosity is fixed to the nominal
value of 36%, but the API mass fraction and hence the mass fraction
of MCC are subject to vary. If we compare the curves of the absorp-
tion coefficients of sets 1 and 3 samples (Fig. 7(a) and (c)) with
almost the same thickness ca. 3 mm, it is obvious that the magni-
tude of the effective absorption coefficient, aeff, is a bit higher in set
3 samples (Fig. 7(c)) than in set 1 samples (Fig. 7(a)). It is quite
interesting that while the API mass fraction is increasing, the
absorption coefficient is decreasing (Fig. 7(c)). A common feature
for all absorption curves (Fig. 7(a), (c) and (e)) is that there is a
‘‘shoulder” toward the high frequencies. As it can be seen from
Fig. 7(c), the shoulder exists already for MCC only (0 wt% API), a
fact that was reported in a previous article [39]. The behavior of
the curves in Fig. 7(c) can be interpreted that the absorption coef-
ficient of MCC is higher than that of the API. In other words,
increasing the wt% of API (i.e. decreasing the wt% of MCC)
decreases the frequency-dependent absorption coefficient of the
pharmaceutical tablet for the case where porosity is constant. In
the case of set 4 samples (Fig. 7(e)), both porosity of tablet and
mass fraction of API and MCC are subject to change. Again, the pro-
nounced absorption role of MCC over API is here manifested
because the change of API wt% is at relatively narrow range of
9–11 wt% compared to the rather wide porosity range of 28–51%.
Anyhow, the observations made above suggest useful information
to pharmaceutical scientists, namely in order to detect a transmis-
sion signal for relatively high absorbing samples, it is possible to
try to find and work within ‘‘spectral window(s)” (e.g. the band
0.1–1.5 THz of this study) where absorption is relatively weak to
allow the transmission of a THz pulse through a relatively thick
pharmaceutical tablet. Generally, the tablet can actually have
strong THz fingerprints in the absorption spectrum, but the key
point is to work on the wings of spectral features where THz
absorption is low enough to allow transmission of the THz pulse.
In order to test the correlation between the effective absorption
coefficient and both the porosity and API mass fraction similar to
the data of Figs. 3 and 6, we took the values of the effective absorp-
tion coefficient of sets 1, 3 and 4 at the frequency of 0.8 THz. We
chose the effective absorption coefficient values at 0.8 THz because
at that frequency value, the recorded change in the frequency-
dependent refractive index values (see Fig. 7(b), (d) and (f)) is
almost the same as the effective refractive index change obtained
from the measured THz pulse delay of the tablet samples (Fig. 3).
A linear correlation was observed between the effective absorption
coefficient and the porosity for sets 1 and 4 samples (see Fig. 8
(a) and (b)). Similarly, there exists a linear correlation between
the effective absorption coefficient and the API mass fraction as
depicted by sets 3 and 4 samples (Fig. 8(c) and (d)). However, by
comparing the magnitude of the slopes, s, of the graphs related
to set 4 samples (Fig. 8(b) and (d)) to their respective counterparts
(Fig. 8(a) and (c)), it was observed that the set 4 samples (i.e. where
both porosity and API mass fraction vary) appear to have higher
slope than sets 1 and 3 (Fig. 8(a) and (c)) in terms of porosity
and API mass fraction respectively. This observation buttresses
our previous assertion that, changing both porosity and API mass
fraction of pharmaceutical tablets has a profound combined effect
on the effective absorption coefficient. In other words, the change
of both porosity and API mass fraction causes strong change in the
effective absorption coefficient than changing only one parameter.
This can be an asset when monitoring of minute change of porosity
and API mass fraction of a tablet. In addition, by comparing the
magnitude of the slopes of the effective absorption coefficient ver-
sus porosity (Fig. 8(a)) and API mass fraction (Fig. 8(c)) for sets 1
and 3 samples respectively, one can infer that the change of only
API mass fraction causes a bit higher change of the effective
absorption coefficient for these samples than changing only the
porosity.
Finally, we discuss the optical strain concept defined in the the-
ory section using experimental data obtained from the study. In
practice, it is quite challenging to simultaneously monitor both
the change of tablet thickness and THz time-delay. Herein, we
briefly deal with the concept of optical strain and compare it with
the conventional true strain using experimental data for simula-
tion purpose. We have used the data of tablet set 4 due to its com-
pression parameters which fit quite well for the purpose of the
simulation. However, for a rigorous measurement of the optical
and conventional strain one should have one single tablet that is
gradually compressed from the initial height to the final height,
and to monitor the changes. In such a case the weight of the tablet
is expected to be a constant. Set 4 samples consist of five different
Fig. 6. Linear correlation observed between the effective refractive index and the API mass fraction of (a) set 3 and (b) set 4 tablet samples.
P. Bawuah et al. / European Journal of Pharmaceutics and Biopharmaceutics 105 (2016) 122–133 129
9. pharmaceutical tablets with almost the same weight and hence,
the best choice for this simulation. We assume that tablet number
5 presents the initial state of the tablet, and this tablet is com-
pressed to the successive porosities (Table 4). Therefore, initial
height of 3.947 mm and initial effective refractive index of 1.405
that correspond to the sample number 5 in Table 4 were used
for the analysis. As it has been shown above, the small change of
API mass fraction has a negligible role on the effective refractive
index change. Instead the relatively big change of porosity is cru-
cial (see Table 4) for the change of the effective refractive index,
and also the strain (different models for porosity-dependent
Young’s modulus were considered in the frame of THz sensing in
[20,22]). Using the height and refractive index data for the tablet
set 4, we have calculated (simulating the compression of a single
tablet to different porosities) eTHz, emech and eopt using Eq. (10)
and Eq. (7) (see Fig. 9(a) and (b) respectively). For the sake of com-
parison, both the conventional true strain, emech, and the optical
strain, eopt, are plotted as a function of height reduction (Fig. 9
(b)). Obviously, both the conventional true strain and the optical
strain parameters have similar functional behavior (the strain is
considered as a positive number). It is therefore possible to
monitor conventional true strain using nondestructive THz time-
delay measurement technique by calibrating the data in Fig. 9.
In principle, the measured data of optical strain could serve as
an indirect method to nondestructively estimate the friability
and dissolution rate of pharmaceutical tablets. Furthermore, infor-
mation on fill fraction ratio of solid medium of the tablet can be
achieved.
Fig. 7. Analysis of the variations of the estimated frequency dependent effective absorption coefficient and effective refractive index of sets 1, 3 and 4 samples. (a) and (b)
Give the respective frequency-dependent absorption coefficient and the effective refractive index for set 1 samples, (c) and (d) show similar data of sets 3 samples whereas (e)
and (f) represent set 4 samples. Both Daeff and Dneff values shown were estimated at 0.8 THz as indicated by the arrows. Numerical values of Daeff and Dneff denote the
difference between maximum and minimum values of the effective absorption coefficient and the effective refractive index, respectively.
130 P. Bawuah et al. / European Journal of Pharmaceutics and Biopharmaceutics 105 (2016) 122–133
10. 5. Conclusions
This study has highlighted the effect of porosity and API mass
fraction on the effective refractive index and effective absorption
coefficient of pharmaceutical tablets using both time-domain and
frequency-domain analytical techniques of transmitted THz waves.
A THz-TD spectrometer in its transmission mode was used for the
measurement. In order to learn how the change in porosity and API
mass fraction affects the optical constants, four training sets (sets
1–4) of real pharmaceutical tablets composed of MCC and indo-
methacin with different compaction parameters were compacted.
It was observed that both the time-domain and frequency-
domain effective refractive index and effective absorption coeffi-
cient have linear correlation with the porosity and API mass frac-
tion even for three-phase pharmaceutical tablets. Though both
porosity and API mass fraction have linear dependence on the opti-
cal constants, it was revealed that, in terms of the effective refrac-
tive index, porosity has dominant effect over the API mass fraction.
Fig. 8. The correlation between the effective absorption coefficient at 0.8 THz and both the porosity (f) and API mass fraction (x) for (a) set 1, (b) set 4, (c) set 3 and (d) set 4.
Fig. 9. (a) Optical strain calculated from measured THz pulse delay as a function of optical path length and (b) absolute value of conventional true strain and optical strain as a
function of change of the optical path length of set 4 tablets.
P. Bawuah et al. / European Journal of Pharmaceutics and Biopharmaceutics 105 (2016) 122–133 131
11. Thus, doubling the change in porosity almost doubled the change
in the effective refractive index. In terms of the effective absorption
coefficient, it was observed that the change in porosity and API
mass fraction has almost similar effect, with the change of API
mass fraction dominating a bit over the change in porosity. How-
ever, a relatively strong combined effect of the change of both
porosity and API mass fraction was observed on the change in
the absorption coefficient of pharmaceutical tablets.
We introduced and demonstrated a 3D plane concept that could
serve as a practical visual tool to monitor the production history of
batches of pharmaceutical tablets in the industrial setting. Addi-
tionally, this 3D plane concept that is based on THz measurement
of training sets of pharmaceutical tablets, in principle, can serve as
a tool for computer-aided design of tablet products, and also for
quality inspection of pharmaceutical tablets.
Furthermore, we have introduced and demonstrated the use of
a novel method that gives information on true strain and change of
fill fraction ratio of solid medium of pharmaceutical tablets by THz
pulse time delay measurement technique.
The promising outcome of this work could serve as a PAT tool
for the fast estimation and monitoring of the porosity and API mass
fraction of pharmaceutical tablets during and after production.
This is the first time we have worked on training samples that
contain API and we look further to the extraction of the weight,
density and height by THz measurement technique. The scope of
this current study is limited to only flat-faced tablets; however,
we envisage the effect of changing the porosity and API mass frac-
tion on the optical constants (that is absorption coefficient and
refractive index) for curved surface tablets as well. The final goal
is to provide both theory and experimental methods to manage
not only with curved tablets but also with pharmaceutical tablets
that strongly absorb THz radiation. In such a case, the reflected
THz signal detected from the tablet’s surface will be a plausible
option to be used for the detection of the properties of pharmaceu-
tical tablets.
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