Pharmaceutical Solid Dosage Forms Research Articles

Continuous manufacturing process monitoring of pharmaceutical solid dosage form: A case study

Continuous Manufacturing (CM) of pharmaceutical drug products is a rather new approach within the pharmaceutical industry. In the presented paper, a GMP continuous wet granulation line used for clinical production of solid dosage forms was investigated with a thorough monitoring strategy regarding process performance and robustness. The line was composed of the subsequent continuous unit operations feeding – twin-screw wet-granulation – fluid-bed drying – sieving and tableting; the formulation of a new pharmaceutical entity in development was selected for this study. In detail, a Design of Experiments (DoE) was used to evaluate the impact of the three main factors (amount of water, filling rate, and shear force in twin-screw granulator) on the tablet quality. The process was monitored via in-process control (IPC) tests (e.g. weight, hardness, disintegration, and loss-on-drying), Process Analytical Technologies (PAT), and through the analysis of the process parameters (multivariate process control). The tested formulation was very robust to the large process variation of the DoE: all IPC results were in specification, the PAT probes provided stable results for the content uniformity and no critical variations can be detected in the process parameters. An adequate monitoring strategy was presented and the robustness of the process with one formulation has been demonstrated. In summary, this continuous process in combination with smart formulation development allows the robust production of constant quality tablets. The synergy between PAT, process data science and IPC creates an adequate monitoring framework of the continuous manufacturing line.

Compatibility study of rosmarinic acid with excipients used in pharmaceutical solid dosage forms using thermal and non-thermal techniques

Rosmarinic acid (RA) is a phenolic compound that presents well-documented anti-inflammatory, antioxidant and antitumor activities, and based on its pharmacological potential and poor bioavailability, several solid dosage forms have been developed to RA delivery. Therefore, in literature, there are no reports about RA compatibility with excipients. In this regard, the aim of the present study was to evaluate, for the first time, the compatibility of RA with excipients commonly used in solid dosage forms at a 1:1 (RA:excipient) ratio using differential scanning calorimetry (DSC), thermogravimetry (TG), Fourier-transform infrared (FTIR), solid-state nuclear magnetic resonance (ssNMR), and isothermal stress testing (IST) coupled with liquid chromatography (LC). The excipients selected were hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose (MCC), lactose monohydrate (LAC), polyvinylpyrrolidone (PVP), talc (TALC), croscarmellose sodium (CCS), and magnesium stearate (MgSTE). According to DSC results, physical interactions were found between RA and HPMC, LAC, CCS, and MgSTE. The TG analyses confirmed the physical interactions and suggested chemical incompatibility. FTIR revealed physical interaction of RA with TALC and MgSTE and the ssNMR confirmed the physical interaction showed by FTIR and excluded the presence of chemical incompatibility. By IST, the greatest loss of RA content was found to CCS and MgSTE (>15%), demonstrating chemical incompatibilities with RA. High temperatures used in DSC and TG analyses could be responsible for incompatibilities in binary mixtures (BMs) with HPMC and LAC, while temperature above 25 °C and presence of water were factors that promote incompatibilities in BMs with CCS and MgSTE. Overall results demonstrate that RA was compatible with MCC and PVP.

An Overview on Tablet Coating

Pharmaceutical solid dosage forms include tablets, pellets, pills, beads etc. Tablet is most commonly used pharmaceutical dosage form which has ease of administration. Tablets are coated for many reason such as masking odour, taste, colour of the drug, providing physical and chemical protection to drug, protecting drug from the gastric environment.Coating is a process by which a layer of coating material is applied to the surface of a dosage form. Coating may also contain active ingredient. There are various strategies for tablet coating which include sugar coating, film coating, and enteric coating. The amount of coating on the surface of a tablet is critical to the effectiveness of the oral dosage form. Recent trends in tablet coating focuses on overcoming disadvantage of solvent based coating. This review concerns with the coating process, equipments involved, coated tablets evaluation and specialized coating techniques.
 
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SIMPLE AND RAPID HPLC METHOD FOR SIMULTANEOUS QUANTIFICATION OF LEVODOPA AND CARBIDOPA IN A FAST DISINTEGRATING TABLET FORMULATION

Objective: Fast disintegrating tablets (FDTs) are found helpful in dysphagia (difficulty in swallowing) especially in Parkinson patients. Levodopa is still the first choice in Parkinson disease treatment and is co-administered by carbidopa for better efficacy.
 Methods: In the present study, a rapid and simple isocratic Reverse Phase-High Performance Liquid Chromatography (RP-HPLC) method was developed and validated for simultaneous quantification of levodopa and carbidopa in optimized Fast Disintegrating Tablets (FDTs). The linearity, precision, accuracy, limit of detection (LOD) and limit of quantification (LOQ) of the method were determined. FDTs were prepared using direct compression, dry and wet granulation and were optimized for faster disintegration time. Tablets thickness, weight, hardness, friability, drug content and dissolution profile were also evaluated.
 Results: A RP-HPLC system with C18 column and mobile phase 90:10 (v/v) phosphate buffer: methanol was used. The method linearity was found to be within the concentration range of 3.125-50 μg/ml for levodopa, and 3.125-25 μg/ml for carbidopa. The intra and inter-day precision and accuracy were acceptable. LOD and LOQ of levodopa-carbidopa were 0.2-0.8 μg/ml and 0.5-2.4 μg/ml, respectively. The total chromatographic run time was 5 min. The optimized FDTs hardness was 3.81±0.4 and tablets were disintegrated within 30 sec. Levodopa and carbidopa were dissolved in dissolution media within 5 min.
 Conclusion: Results indicated that this method was suitable for simultaneous quantification of levodopa and carbidopa in the presence of different ingredients of a pharmaceutical solid dosage form. Therefore, this method could be applied in pharmaceutical quality control for rapid quantification of structurally similar substances with different physicochemical properties.

Elucidation of the Controlled-Release Behavior of Metoprolol Succinate from Directly Compressed Xanthan Gum/Chitosan Polymers: Computational and Experimental Studies.

The development and evaluation of a controlled-release (CR) pharmaceutical solid dosage form comprising xanthan gum (XG), low molecular weight chitosan (LCS), and metoprolol succinate (MS) are reported. The research is, partly, based upon the utilization of computational tools: in this case, molecular dynamics simulations (MDs) and the response surface method (RSM) in order to underpin the design/prediction and to minimize the experimental work required to achieve the desired pharmaceutical outcomes. The capability of the system to control the release of MS was studied as a function of LCS (% w/w) and total polymer (LCS and xanthan gum (XG)) to drug ratio (P/D) at different tablet tensile strengths. MDs trajectories, obtained by using different ratios of XG/LCS as well as XG and high molecular weight chitosan (HCS), showed that the driving force for the interaction between XG and LCS is electrostatic in nature, the most favorable complex is formed when LCS is used at 15% (w/w) and, importantly, the interaction between XG and LCS is more favorable than that between XG and HCS. RSM outputs revealed that the release of the drug from the LCS/XG matrix is highly dependent on both the % LCS and the P/D ratio and that the required CR effect can be achieved when using weight fractions of LCS ≤ 20% and P/D ratios ≥2.6:1. Results obtained from in vitro drug release and swelling studies on the prepared tablets showed that using LCS at the weight fractions suggested by MDs and RSM data plays a major role in overcoming the high sensitivity of the controlled drug release effect of XG on ionic strength and pH changes of the dissolution media. In addition, it was found that polymer relaxation is the major contributor to the release of MS from LCS/XG tablets. Using Raman spectroscopy, MS was shown to be localized more in the core of the tablets at the initial stages of dissolution due to film formation between LCS and XG on the tablet surface, which prevents excess water penetration into the matrix. In the later stages of the dissolution process, the film starts to dissolve/erode, allowing full tablet hydration and a uniform drug distribution in the swollen tablet.

Raman Spectroscopy for Process Analytical Technologies of Pharmaceutical Secondary Manufacturing.

As the process analytical technology (PAT) mindset is progressively introduced and adopted by the pharmaceutical companies, there is an increasing demand for effective and versatile real-time analyzers to address the quality assurance challenges of drug manufacturing. In the last decades, Raman spectroscopy has emerged as one of the most promising tools for non-destructive and fast characterization of the pharmaceutical processes. This review summarizes the achieved results of the real-time application of Raman spectroscopy in the field of the secondary manufacturing of pharmaceutical solid dosage forms, covering the most common secondary process steps of a tablet production line. In addition, the feasibility of Raman spectroscopy for real-time control is critically reviewed, and challenges and possible approaches to moving from real-time monitoring to process analytically controlled technologies (PACT) are discussed.

Study of Pharmaceutical Solid dosage forms using Invasive and Non Invasive Techniques: A Review

Study of Pharmaceutical Solid dosage forms using Invasive and Non Invasive Techniques: A Review

Computational methods in preformulation study for pharmaceutical solid dosage forms of therapeutic proteins

AbstractDesign and delivery of protein-based biopharmaceuticals needs detailed planning and strict monitoring of intermediate processing steps, storage conditions and container-closure system to ensure a stable, elegant and biopharmaceutically acceptable dosage form. Selection of manufacturing process variables and conditions along with packaging specifications can be achieved through properly designed preformulation study protocol for the formulation. Thermodynamic stability and biological activity of therapeutic proteins depend on folding–unfolding and three-dimensional packing dynamics of amino acid network in the protein molecule. Lack of favourable environment may cause protein aggregation with loss in activity and even fatal immunological reaction. Although lyophilization can enhance the stability of protein-based formulations in the solid state, it can induce protein unfolding leading to thermodynamic instability. Formulation stabilizers such as preservatives can also result in aggregation of therapeutic proteins. Modern instrumental techniques in conjunction with computational tools enable rapid and accurate prediction of amino acid sequence, thermodynamic parameters associated with protein folding and detection of aggregation “hot-spots.” Globular proteins pose a challenge during investigations on their aggregation propensity. Biobetter therapeutic monoclonal antibodies with enhanced stability, solubility and reduced immunogenic potential can be designed through mutation of aggregation-prone zones. The objective of the present review article is to focus on the various analytical methods and computational approaches used in the study of thermodynamic stability and aggregation tendency of therapeutic proteins, with an aim to develop optimal and marketable formulation. Knowledge of protein dynamics through application of computational tools will provide the essential inputs and relevant information for successful and meaningful completion of preformulation studies on solid dosage forms of therapeutic proteins.

Inclusion complex of amiodarone hydrochloride with cyclodextrins: preparation, characterization and dissolution rate evaluation

This study aimed to improve the water solubility of amiodarone hydrochloride (AMH) via inclusion complexes with β-cyclodextrin, methyl-β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin. Inclusion complexes were developed by physical mixture, coevaporation, spray-drying and freeze-drying. Solid state analysis was performed using X-ray powder diffraction, differential scanning calorimetry and scanning electronic microscopy. Thermodynamic studies demonstrate that the inclusion complexes of drug into different cyclodextrins were an exothermic process that occurred spontaneously. Water solubility and drug dissolution rates were significantly increased after the formation of inclusion complexes with the cyclodextrins evaluated in relation to the physical mixture and pure drug. The present study provides useful information for the potential application of complexation with amiodarone HCl. This may be a good strategy for the development of solid pharmaceutical dosage forms.

Unveiling multiple solid-state transitions in pharmaceutical solid dosage forms using multi-series hyperspectral imaging and different curve resolution approaches

Solid-state transitions at the surface of pharmaceutical solid dosage forms (SDF) were monitored using multi-series hyperspectral imaging (HSI) along with Multivariate Curve Resolution – Alternating Least Squares (MCR-ALS) and Parallel Factor Analysis (PARAFAC and PARAFAC2). First, the solid-state transformation due to the dehydration of the monohydrate forms of piroxicam and lactose to their respective anhydrate counterparts in tablets were monitored using temperature series NIR-HSI. PARAFAC and MCR-ALS solutions were hampered by the lack of strict trilinearity of the pixels among the unfolded series NIR-images (three-way array) and due to rotational ambiguity (augmented matrix), respectively, while PARAFAC2 resolved satisfactorily the profile of the corresponding compounds in the pixels in the series NIR-images. Next, the amorphous-to-crystalline transitions were monitored in solid dispersion of indomethacin with polyvinylpyrrolidone using time series MIR-HSI. MCR-ALS properly resolved the known solid-state forms of the drug in the pixels of the series MIR-images, while PARAFAC and PARAFAC2 failed to properly resolve all the drug forms in the series MIR-images due to i) strict trilinearity leak in the three-way array and ii) the mandatory constant cross-product AkTAk over the k series MIR-images (A is the loadings of the shift mode), respectively. The highlighting of the advantages and limitation of the corresponding curve resolution methods stressed their potential applicability when handling multi-series HSI to study solid-state transitions in pharmaceutical SDFs.

HILIC-MS/MS Method for Analysis of Ephedrine in Internet-available Drugs

A new separation method involving hydrophilic interaction liquid chromatography with tandem mass spectrometric detection has been developed for the analysis of ephedrine in a pharmaceutical solid dosage form. The optimized conditions for the analysis of ephedrine consisted of an Acquity BEH Amide column, and a mobile phase composed of acetonitrile/5 mM ammonium formate, pH 3.0, 88/12 (v/v), flow rate 0.4 mL min−1 and column temperature 30 °C. The developed analytical procedure provides high throughput of samples where LC analysis takes only 90 s. Detection was performed by tandem mass spectrometry using electrospray ionization in multiple reaction monitoring mode. This method was found to be precise, linear, accurate, sensitive, selective and robust for routine application in screening of commercial pharmaceutical products based on the content of ephedrine. Application of the method for the determination of ephedrine content in 20 different pharmaceutical drug products revealed that 5 samples did not contain any ephedrine at all, 3 samples contained lower dosage than declared, and the dosage in 1 sample was exceeded.

Classical Least Squares Combined with Spectral Interval Selection Using Genetic Algorithm for Prediction of Constituents in Pharmaceutical Solid Dosage Forms from near Infrared Chemical Imaging Data

A new algorithm that combines spectral interval selection using genetic algorithm and classical least squares (GA-iCLS) is presented for the prediction of the active pharmaceutical ingredients and excipients in various pharmaceutical solid dosage forms from near infrared chemical imaging data. The algorithm is based on the CLS approach, selecting the best wavenumber intervals in the unfolded hyper-cube of each sample (D), and in pure-compound reference spectra (S), wherein the pixel-to-pixel prediction capability of the compounds, obtained by C = DST(SST)−1, is optimised for the samples. The wavelength intervals were selected (GA optimisation) while minimising the error between the mean concentrations of the ith compound predicted in the pixels and the nominal concentration in the corresponding sample (known a priori). The excluded wavenumber intervals from D (and S), for each sample, were interpreted based on systematic deviations from D = CST + E (CLS approach) due to the scattering effects and/or intermolecular interactions in mixtures of the pure compounds. The comparison of the chemical images generated from the predictions performed using the GA-iCLS algorithms with similar images obtained without spectral interval selection, using direct CLS and multivariate curve resolution–alternating least squares, revealed the potential applicability of the proposed algorithm for analytical purposes for pharmaceuticals using chemical imaging data.

Linking granulation performance with residence time and granulation liquid distributions in twin-screw granulation: An experimental investigation

Twin-screw granulation is a promising wet granulation technique for the continuous manufacturing of pharmaceutical solid dosage forms. A twin screw granulator displays a short residence time. Thus, the solid–liquid mixing must be achieved quickly by appropriate arrangement of transport and kneading elements in the granulator screw allowing the production of granules with a size distribution appropriate for tableting. The distribution of residence time and granulation liquid is governed by the field conditions (such as location and length of mixing zones) in the twin-screw granulator, thus contain interesting information on granulation time, mixing and resulting sub-processes such as wetting, aggregation and breakage. In this study, the impact of process (feed rate, screw speed and liquid-to-solid ratio) and equipment parameters (number of kneading discs and stagger angle) on the residence time (distribution), the granulation liquid-powder mixing and the resulting granule size distributions during twin-screw granulation were investigated. Residence time and axial mixing data was extracted from tracer maps and the solid–liquid mixing was quantified from moisture maps, obtained by monitoring the granules at the granulator outlet using near infra-red chemical imaging (NIR-CI). The granule size distribution was measured using the sieving method. An increasing screw speed dominantly reduced the mean residence time. Interaction of material throughput with the screw speed and with the number of kneading discs led to most variation in the studied responses including residence time and mixing capacity. At a high screw speed, granulation yield improved due to high axial mixing. However, increasing material throughput quickly lowers the yield due to insufficient mixing of liquid and powder. Moreover, increasing liquid-to-solid ratio resulted in more oversized granules, and the fraction of oversized granules further increased at higher throughput. Although an increasing number of kneading discs was found to be critical for achieving a uniform distribution of the granulation liquid, the granulation performance was hampered due to insufficient solid–liquid mixing capacity of the current kneading discs which is essential for wet granulation. Thus, a balance between material throughput and screw speed should be strived for in order to achieve a specific granulation time and solid–liquid mixing for high granulation yield. Additionally, more efforts are needed both in modification of the screw configuration as well as the geometry of the mixing elements to improve the mixing capacity of the twin-screw granulator. The results from the current experimental study improved the understanding regarding the interplay between granulation time and the axial and solid–liquid mixing responsible for the granulation performance in twin-screw wet granulation.

Spectroscopic Techniques for Nondestructive Quality Inspection of Pharmaceutical Products: A Review

, 2015Spectroscopy is an emerging technology for the quality assessment of pharmaceutical samples, from tablet manufacturing to final quality assurance. The traditional methods for the quality management of pharmaceutical tablets are time consuming and destructive, while spectroscopic techniques allow rapid analysis in a non-destructive manner. The advantage of spectroscopy is that it collects both spatial and spectral information (called hyperspectral imaging), which is useful for the chemical imaging of pharmaceutical samples. These chemical images provide both qualitative and quantitative information on tablet samples. In the pharmaceutics, spectroscopic techniques are used for a variety of applications, such as analysis of the homogeneity of powder samples as well as determination of particle size, product composition, and the concentration, uniformity, and distribution of the active pharmaceutical ingredient in solid tablets. This review paper presents an introduction to the applications of various spectroscopic techniques such as hyperspectroscopy and vibrational spectroscopies (Raman spectroscopy, FT-NIR, and IR spectroscopy) for the quality and safety assessment of pharmaceutical solid dosage forms. In addition, various chemometric techniques that are highly essential for analyzing the spectroscopic data of pharmaceutical samples are also reviewed.Keywords: Applications, Chemometrics, Hyperspectroscopy, Pharmaceutical, Vibrational spectroscopy

Particle Engineering Via Mechanical Dry Coating in the Design of Pharmaceutical Solid Dosage Forms.

Cohesive powders are problematic in the manufacturing of pharmaceutical solid dosage forms because they exhibit poor flowability, fluidization and aerosolization. These undesirable bulk properties of cohesive powders represent a fundamental challenge in the design of efficient pharmaceutical manufacturing processes. Recently, mechanical dry coating has attracted increasing attention as it can improve the bulk properties of cohesive powders in a cheaper, simpler, safer and more environment-friendly way than the existing solvent-based counterparts. In this review, mechanical dry coating techniques are outlined and their potential applications in formulation and manufacturing of pharmaceutical solid dosage forms are discussed. Reported data from the literature have shown that mechanical dry coating holds promise for the design of superior pharmaceutical solid formulations or manufacturing processes by engineering the interfaces of cohesive powders in an efficient and economical way.

Continuous manufacturing: the future in pharmaceutical solid dosage form manufacturing

Continuous manufacturing: the future in pharmaceutical solid dosage form manufacturing

Quantification of segregation potential for polydisperse, cohesive, multi-component powders and prediction of tablet die-filling performance – A methodology for practical testing, re-formulation and process design

The tendency of powder mixtures to demix due to segregation is a substantial technical concern for manufacturing of pharmaceutical solid dosage forms. In this paper, a methodology for quantifying the maximum potential segregation, as well as predicting the actual, segregation of a powder blend is outlined. The method begins with measurement of the sieve assay profile of the blend. Individual component and overall size segregation indices are defined in terms of overlap integral calculations that characterize the maldistribution of the components among the sieve fractions. This approach has been in use since 2001 at Merck & Co. for multicomponent polydisperse pharmaceutical powder blends and is appropriate for direct compression blends and agglomerated systems, including ordered mixtures. Die-filling performance can be predicted when the individual maldistribution index (Di) is combined with blend flowability (gravity-normalized cohesivity) on a regime map. This map strongly confirms that better blend flowability increases segregation realization. The approach permits rational risk assessment for existing product changes and optimization of new formulations. Analysis assumptions are discussed and deemed to be conservative with respect to prediction of demixing.

Physicochemical and tablet properties of Cyperus alulatus rhizomes starch granules

The starch extracted from rhizomes of Cyperus alulatus (CA) was characterized for its physicochemical, morphological and tableting properties. Rhizomes of CA yield a significant quantity of starch granules (CASG) i.e., 11.93%. CASG was characterized in terms of moisture, ash and amylose contents, solubility and swelling power, paste clarity and water retention capacity. The swelling power was found to be significantly improved with the increase in temperature. Scanning electron micrographs revealed that the granule's surface was smooth, the granules were spherical, mostly round, disc like, and the size range was 6.65–12.13μm. Finger print region in FTIR spectra confirmed its carbohydrate nature. The evaluated micromeritic properties of extracted granule's bulk density, tapped density, Carr's index, Hausner ratio, true density and porosity render unique practicability of CASG being used as an adjuvant in pharmaceutical solid dosage forms. Tablets prepared by using CASG showed higher mechanical strength and more disintegration time, which depicted the characteristic binding nature of the starch granules. As CASG is imparting better binding properties in less concentration and also it can be used in combination with the established starches to get the synergistic effect; this starch can be used commercially in the tablet preparation.

Analytical Method Validation of Simultaneous Determination of Spironolactone and Furosemide in Tablet Formulation and its Statistical Evaluation

The objective of current study was to Statistical Comparison for Precision and Intermediate Precision study for Analytical Method Validation of Spironolactone and Furosemide in tablet formulation and developed easy, exact and correct isocratic stability indicating reversed phase HPLC assay method and validated for determination of Spironolactone and Furosemide in solid pharmaceutical dosage forms. Isocratic RP-HPLC separation was achieved on an SGE make 150 4.6mm SS Wakosil II 5C18RS 5 μm column (Part Number: 206610 and Serial Number: A01-063) using mobile phase of Acetonitrile- Ammonium acetate buffer (50:50, v/v) at a flow rate of 1.1 ml/min and the detection was carried out at 254 nm using photo-diode array detector. The method was validated for specificity, linearity, precision, accuracy, robustness and solution stability. The method was linear in the drug concentration range of 40-160 µg/ml with a correlation coefficient 0.9977 and 0.9953 for Spironolactone and Furosemide respectively. The precision (RSD) amongst six-sample preparation was 0.87% and 1.1 % for Spironolactone and Furosemide respectively. For repeatability and intermediate precision (RSD) amongst six-sample preparation was 0.46 % and 0.20 % for Spironolactone and Furosemide respectively. As result shown that for furosemide, % RSD was 1.12% and in ANOVA study Significance F value found 0.625502408 and for spironolactone Precision study and Intermediate precision study % RSD was 0.68, in ANOVA study Significance F value found 0.905843808.

Analytical Method Validation of Simultaneous Determination of Spironolactone and Furosemide in Tablet Formulation and its Statistical Evaluation

The objective of current study was to Statistical Comparison for Precision and Intermediate Precision study for Analytical Method Validation of Spironolactone and Furosemide in tablet formulation and developed easy, exact and correct isocratic stability indicating reversed phase HPLC assay method and validated for determination of Spironolactone and Furosemide in solid pharmaceutical dosage forms. Isocratic RP-HPLC separation was achieved on an SGE make 150 4.6mm SS Wakosil II 5C18RS 5 μm column (Part Number: 206610 and Serial Number: A01-063) using mobile phase of Acetonitrile- Ammonium acetate buffer (50:50, v/v) at a flow rate of 1.1 ml/min and the detection was carried out at 254 nm using photo-diode array detector. The method was validated for specificity, linearity, precision, accuracy, robustness and solution stability. The method was linear in the drug concentration range of 40-160 µg/ml with a correlation coefficient 0.9977 and 0.9953 for Spironolactone and Furosemide respectively. The precision (RSD) amongst six-sample preparation was 0.87% and 1.1 % for Spironolactone and Furosemide respectively. For repeatability and intermediate precision (RSD) amongst six-sample preparation was 0.46 % and 0.20 % for Spironolactone and Furosemide respectively. As result shown that for furosemide, % RSD was 1.12% and in ANOVA study Significance F value found 0.625502408 and for spironolactone Precision study and Intermediate precision study % RSD was 0.68, in ANOVA study Significance F value found 0.905843808.