Dissolution and Disintegration of Oral Solid Dosage Forms

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Physical Pharmacy and Formulation".

Deadline for manuscript submissions: closed (10 March 2023) | Viewed by 23845

Special Issue Editors

Department of Chemical and Biological Engineering, The University of Sheffield, Sheffield S10 2TN, UK
Interests: powders; particles; granulation; mechanistic modelling; process; population balance modelling; discrete element modelling; dissolution; disintegration
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G1 1RD, UK
Interests: terahertz spectroscopy and imaging; optical coherence tomography; pharmaceutical applications; process monitoring; quality control
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Special Issue Information

Dear Colleagues,

The disintegration and dissolution behaviour of solid oral dosage forms (tablets, capsules and dispersions) is an essential performance measure for all medicines.  As available manufacturing methods for medicines diversify the level of control over intermediate (e.g. granules and spherical agglomerates) and final product microstructures is improving, and with it the ability to control disintegration and dissolution performance.  There is increasing opportunity to design formulations and manufacturing methods to achieve desired release profiles, however the mechanisms behind dosage form disintegration and dissolution are complex and their link to raw material attributes, formulations, manufacturing and storage conditions are not fully understood. 

In this special issue, contributions are invited which further the understanding, prediction and measurement of disintegration and dissolution of solid oral dosage forms.  Of particular interest are studies which investigate the complex interactions of materials, formulations, manufacturing, storage and the disintegration and dissolution performance, and also those with proposed mechanistic models to explain and predict drug release phenomena. 

Dr. Rachel Smith
Dr. Daniel Markl
Guest Editors

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Keywords

  • tablet
  • capsule
  • dissolution
  • disintegration
  • in vitro

Published Papers (9 papers)

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Research

20 pages, 6673 KiB  
Article
Development of a Discriminative Dissolution Method, Using In-Silico Tool for Hydrochlorothiazide and Valsartan Tablets
by Rosmery Merma Leon, Michele Georges Issa, Marcelo Dutra Duque, Josiane Souza Pereira Daniel and Humberto Gomes Ferraz
Pharmaceutics 2023, 15(6), 1735; https://doi.org/10.3390/pharmaceutics15061735 - 14 Jun 2023
Viewed by 1863
Abstract
Hydrochlorothiazide (HTZ) and Valsartan (VAL) are poorly soluble drugs in BCS classes IV and II. This study aimed to develop a method to assess the dissolution profile of tablets containing HTZ (12.5 mg) and VAL (160 mg) as a fixed-dose combination, using in [...] Read more.
Hydrochlorothiazide (HTZ) and Valsartan (VAL) are poorly soluble drugs in BCS classes IV and II. This study aimed to develop a method to assess the dissolution profile of tablets containing HTZ (12.5 mg) and VAL (160 mg) as a fixed-dose combination, using in silico tools to evaluate products marketed in Brazil and Peru. Firstly, in vitro dissolution tests were performed using a fractional factorial design 33−1. Then, DDDPlus™ was used to carry out experimental design assays of a complete factorial design 33. Data from the first stage were used to obtain calibration constants for in silico simulations. The factors used in both designs were formulation, sinker use, and rotation speed. Finally, effects and factor interaction assessment was evaluated based on a statistical analysis of the dissolution efficiency (DE) obtained from simulations. Thus, the established final conditions of the dissolution method were 900 mL of phosphate buffer pH 6.8, 75 rpm of rotation speed, and sinker use to prevent formulation floating. The reference product stood out because of its higher DE than other formulations. It was concluded that the proposed method, in addition to ensuring total HTZ and VAL release from formulations, has adequate discriminative power. Full article
(This article belongs to the Special Issue Dissolution and Disintegration of Oral Solid Dosage Forms)
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14 pages, 5871 KiB  
Article
Development of Biopredictive Dissolution Method for Extended-Release Desvenlafaxine Tablets
by Gustavo Vaiano Carapeto, Marcelo Dutra Duque, Michele Georges Issa and Humberto Gomes Ferraz
Pharmaceutics 2023, 15(5), 1544; https://doi.org/10.3390/pharmaceutics15051544 - 19 May 2023
Cited by 4 | Viewed by 1521
Abstract
This study aimed to develop a biopredictive dissolution method for desvenlafaxine ER tablets using design of experiments (DoE) and physiologically based biopharmaceutics modeling (PBBM) to address the challenge of developing generic drug products by reducing the risk of product failure in pivotal bioequivalence [...] Read more.
This study aimed to develop a biopredictive dissolution method for desvenlafaxine ER tablets using design of experiments (DoE) and physiologically based biopharmaceutics modeling (PBBM) to address the challenge of developing generic drug products by reducing the risk of product failure in pivotal bioequivalence studies. For this purpose, a PBBM was developed in GastroPlus® and combined with a Taguchi L9 design, to evaluate the impact of different drug products (Reference, Generic #1 and Generic #2) and dissolution test conditions on desvenlafaxine release. The influence of the superficial area/volume ratio (SA/V) of the tablets was observed, mainly for Generic #1, which presented higher SA/V than the others, and a high amount of drug dissolved under similar test conditions. The dissolution test conditions of 900 mL of 0.9% NaCl and paddle at 50 rpm with sinker showed to be biopredictive, as it was possible to demonstrate virtual bioequivalence for all products, despite their release-pattern differences, including Generic #3 as an external validation. This approach led to a rational development of a biopredictive dissolution method for desvenlafaxine ER tablets, providing knowledge that may help the process of drug product and dissolution method development. Full article
(This article belongs to the Special Issue Dissolution and Disintegration of Oral Solid Dosage Forms)
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21 pages, 5842 KiB  
Article
Design and Development of Sublingual Printlets Containing Domperidone Nanocrystals Using 3D Melting Solidification Printing Process (MESO-PP)
by Lucía Lopez-Vidal, Alejandro J. Paredes, Santiago Daniel Palma and Juan Pablo Real
Pharmaceutics 2023, 15(5), 1459; https://doi.org/10.3390/pharmaceutics15051459 - 10 May 2023
Cited by 1 | Viewed by 1488
Abstract
Domperidone (DOM) is a drug commonly used to treat nausea and vomiting, as well as gastrointestinal disorders. However, its low solubility and extensive metabolism pose significant administration challenges. In this study, we aimed to improve DOM solubility and avoid its metabolism by developing [...] Read more.
Domperidone (DOM) is a drug commonly used to treat nausea and vomiting, as well as gastrointestinal disorders. However, its low solubility and extensive metabolism pose significant administration challenges. In this study, we aimed to improve DOM solubility and avoid its metabolism by developing nanocrystals (NC) of DOM through a 3D printing technology—melting solidification printing process (MESO-PP)—to be delivered via a solid dosage form (SDF) that can be administered sublingually. We obtained DOM-NCs using the wet milling process and designed an ultra-rapid release ink (composed of PEG 1500, propylene glycol, sodium starch glycolate, croscarmellose sodium, and sodium citrate) for the 3D printing process. The results demonstrated an increase in the saturation solubility of DOM in both water and simulated saliva without any physicochemical changes in the ink as observed by DSC, TGA, DRX, and FT-IR. The combination of nanotechnology and 3D printing technology enabled us to produce a rapidly disintegrating SDF with an improved drug-release profile. This study demonstrates the potential of developing sublingual dosage forms for drugs with low aqueous solubility using nanotechnology and 3D printing technology, providing a feasible solution to the challenges associated with the administration of drugs with low solubility and extensive metabolism in pharmacology. Full article
(This article belongs to the Special Issue Dissolution and Disintegration of Oral Solid Dosage Forms)
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17 pages, 2223 KiB  
Article
Development of a Swellable and Floating Gastroretentive Drug Delivery System (sfGRDDS) of Ciprofloxacin Hydrochloride
by Yu-Kai Liang, Wen-Ting Cheng, Ling-Chun Chen, Ming-Thau Sheu and Hong-Liang Lin
Pharmaceutics 2023, 15(5), 1428; https://doi.org/10.3390/pharmaceutics15051428 - 07 May 2023
Cited by 2 | Viewed by 2472
Abstract
Sangelose® (SGL) is a novel hydroxypropyl methylcellulose (HPMC) derivative that has been hydrophobically modified. Due to its high viscosity, SGL has the potential as a gel-forming and release-rate-controlled material for application in swellable and floating gastroretentive drug delivery systems (sfGRDDS). [...] Read more.
Sangelose® (SGL) is a novel hydroxypropyl methylcellulose (HPMC) derivative that has been hydrophobically modified. Due to its high viscosity, SGL has the potential as a gel-forming and release-rate-controlled material for application in swellable and floating gastroretentive drug delivery systems (sfGRDDS). The aim of this study was to develop ciprofloxacin (CIP)-loaded sfGRDDS tablets comprised of SGL and HPMC in order to extend CIP exposure in the body and achieve optimal antibiotic treatment regimes. Results illustrated that SGL-HPMC-based sfGRDDS could swell to a diameter above 11 mm and showed a short floating lag time (<4 s) and long total floating time (>24 h) to prevent gastric emptying. In dissolution studies, CIP-loaded SGL-HPMC sfGRDDS demonstrated a specific biphasic release effect. Among the formulations, the SGL/type-K HPMC 15,000 cps (HPMC 15K) (50:50) group exhibited typical biphasic release profiles, with F4-CIP and F10-CIP individually releasing 72.36% and 64.14% CIP within 2 h dissolution, and sustaining release to 12 h. In pharmacokinetic studies, the SGL-HPMC-based sfGRDDS demonstrated higher Cmax (1.56–1.73 fold) and shorter Tmax (0.67 fold) than HPMC-based sfGRDDS. Furthermore, SGL 90L in GRDDS indicated an excellent biphasic release effect and a maximum elevation of relative bioavailability (3.87 fold). This study successfully combined SGL and HPMC to manufacture sfGRDDS that retain CIP in the stomach for an optimal duration while improving its pharmacokinetic characteristics. It was concluded that the SGL-HPMC-based sfGRDDS is a promising biphasic antibiotic delivery system that can both rapidly achieve the therapeutic antibiotic concentration and maintain the plasma antibiotic concentration for an extended period to maximize antibiotic exposure in the body. Full article
(This article belongs to the Special Issue Dissolution and Disintegration of Oral Solid Dosage Forms)
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19 pages, 10878 KiB  
Article
Modelling the Evolution of Pore Structure during the Disintegration of Pharmaceutical Tablets
by Mithushan Soundaranathan, Mohammed Al-Sharabi, Thomas Sweijen, Prince Bawuah, J. Axel Zeitler, S. Majid Hassanizadeh, Kendal Pitt, Blair F. Johnston and Daniel Markl
Pharmaceutics 2023, 15(2), 489; https://doi.org/10.3390/pharmaceutics15020489 - 01 Feb 2023
Cited by 3 | Viewed by 2341
Abstract
Pharmaceutical tablet disintegration is a critical process for dissolving and enabling the absorption of the drug substance into the blood stream. The tablet disintegration process consists of multiple connected and interdependent mechanisms: liquid penetration, swelling, dissolution, and break-up. One key dependence is the [...] Read more.
Pharmaceutical tablet disintegration is a critical process for dissolving and enabling the absorption of the drug substance into the blood stream. The tablet disintegration process consists of multiple connected and interdependent mechanisms: liquid penetration, swelling, dissolution, and break-up. One key dependence is the dynamic change of the pore space in a tablet caused by the swelling of particles while the tablet takes up liquid. This study analysed the changes in the pore structure during disintegration by coupling the discrete element method (DEM) with a single-particle swelling model and experimental liquid penetration data from terahertz-pulsed imaging (TPI). The coupled model is demonstrated and validated for pure microcrystalline cellulose (MCC) tablets across three porosities (10, 15, and 22%) and MCC with three different concentrations of croscarmellose sodium (CCS) (2, 5, and 8% w/w). The model was validated using experimental tablet swelling from TPI. The model captured the difference in the swelling behaviour of tablets with different porosities and formulations well. Both the experimental and modelling results showed that the swelling was lowest (i.e., time to reach the maximum normalised swelling capacity) for tablets with the highest CCS concentration, cCCS = 8%. The simulations revealed that this was caused by the closure of the pores in both the wetted volume and dry volume of the tablet. The closure of the pores hinders the liquid from accessing other particles and slows down the overall swelling process. This study provides new insights into the changes in the pore space during disintegration, which is crucial to better understand the impact of porosity and formulations on the performance of tablets. Full article
(This article belongs to the Special Issue Dissolution and Disintegration of Oral Solid Dosage Forms)
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16 pages, 14824 KiB  
Article
Development of Flow-Through Cell Dissolution Method for In Situ Visualization of Dissolution Processes in Solid Dosage Forms Using X-ray μCT
by Niloofar Moazami Goudarzi, Aseel Samaro, Chris Vervaet and Matthieu N. Boone
Pharmaceutics 2022, 14(11), 2475; https://doi.org/10.3390/pharmaceutics14112475 - 16 Nov 2022
Cited by 6 | Viewed by 1483
Abstract
Visualization of the dynamic behavior of pharmaceutical dosage forms during the dissolution process offers a better understanding of the drug release mechanism, enabling the design of customized dosage forms. In this study, an X-ray tomography-based approach is proposed to monitor and analyze the [...] Read more.
Visualization of the dynamic behavior of pharmaceutical dosage forms during the dissolution process offers a better understanding of the drug release mechanism, enabling the design of customized dosage forms. In this study, an X-ray tomography-based approach is proposed to monitor and analyze the dynamics of the structure at the pore scale level during the dissolution process. A flow-through cell dissolution apparatus was developed, capable of mimicking the standard in vitro dissolution process, which can be easily positioned in an X-ray tomography setup. The method was utilized to study the dissolution of a Capa® (polycaprolactone)-based sustained-release 3D printed tablet. The impact of the flow rate on the active pharmaceutical ingredient (API) release rate was studied and 16 mL/min was selected as a suitable flow rate. Furthermore, cesium chloride (CsCl) was used as a contrast agent to increase the contrast between the sample and the dissolution medium. Data obtained with this novel technique were in a good agreement with the released drug rate acquired by the standard in vitro dissolution test (the similarity factor (f2) = 77%). Finally, the proposed approach allowed visualizing the internal structure of the sample, as well as real-time tracking of solution ingress into the product. Full article
(This article belongs to the Special Issue Dissolution and Disintegration of Oral Solid Dosage Forms)
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25 pages, 6600 KiB  
Article
Tablet Disintegration and Dispersion under In Vivo-like Hydrodynamic Conditions
by Jan Lenz, Frederik Fuest, Jan Henrik Finke, Heike Bunjes, Arno Kwade and Michael Juhnke
Pharmaceutics 2022, 14(1), 208; https://doi.org/10.3390/pharmaceutics14010208 - 16 Jan 2022
Cited by 2 | Viewed by 3378
Abstract
Disintegration and dispersion are functional properties of tablets relevant for the desired API release. The standard disintegration test (SDT) described in different pharmacopoeias provides only limited information on these complex processes. It is considered not to be comparable to the biorelevant conditions due [...] Read more.
Disintegration and dispersion are functional properties of tablets relevant for the desired API release. The standard disintegration test (SDT) described in different pharmacopoeias provides only limited information on these complex processes. It is considered not to be comparable to the biorelevant conditions due to the frequent occurrence of high hydrodynamic forces, among other reasons. In this study, 3D tomographic laser-induced fluorescence imaging (3D Tomo-LIF) is applied to analyse tablet disintegration and dispersion. Disintegration time (DT) and time-resolved particle size distribution in close proximity to the tablet are determined in a continuously operated flow channel, adjustable to very low fluid velocities. A case study on tablets of different porosity, which are composed of pharmaceutical polymers labelled with a fluorescent dye, a filler, and disintegrants, is presented to demonstrate the functionality and precision of the novel method. DT results from 3D Tomo-LIF are compared with results from the SDT, confirming the analytical limitations of the pharmacopoeial disintegration test. Results from the 3D Tomo-LIF method proved a strong impact of fluid velocity on disintegration and dispersion. Generally, shorter DTs were determined when cross-linked sodium carboxymethly cellulose (NaCMCXL) was used as disintegrant compared to polyvinyl polypyrrolidone (PVPP). Tablets containing Kollidon VA64 were found to disintegrate by surface erosion. The novel method provides an in-depth understanding of the functional behaviour of the tablet material, composition and structural properties under in vivo-like hydrodynamic forces regarding disintegration and the temporal progress of dispersion. We consider the 3D Tomo-LIF in vitro method to be of improved biorelevance in terms of hydrodynamic conditions in the human stomach. Full article
(This article belongs to the Special Issue Dissolution and Disintegration of Oral Solid Dosage Forms)
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16 pages, 1543 KiB  
Article
The Influence of Omeprazole on the Dissolution Processes of pH-Dependent Magnetic Tablets Assessed by Pharmacomagnetography
by Guilherme A. Soares, Deivid W. Pires, Leonardo A. Pinto, Gustavo S. Rodrigues, André G. Prospero, Gabriel G. A. Biasotti, Gabriela N. Bittencourt, Erick G. Stoppa, Luciana A. Corá, Ricardo B. Oliveira and José R. A. Miranda
Pharmaceutics 2021, 13(8), 1274; https://doi.org/10.3390/pharmaceutics13081274 - 17 Aug 2021
Cited by 6 | Viewed by 2615
Abstract
Pharmacomagnetography involves the simultaneous assessment of solid dosage forms (SDFs) in the human gastrointestinal (GI) tract and the drug plasmatic concentration, using a biomagnetic technique and pharmacokinetics analysis. This multi-instrumental approach helps the evaluation, as GI variables can interfere with the drug delivery [...] Read more.
Pharmacomagnetography involves the simultaneous assessment of solid dosage forms (SDFs) in the human gastrointestinal (GI) tract and the drug plasmatic concentration, using a biomagnetic technique and pharmacokinetics analysis. This multi-instrumental approach helps the evaluation, as GI variables can interfere with the drug delivery processes. This study aimed to employ pharmacomagnetography to evaluate the influence of omeprazole on the drug release and absorption of metronidazole administered orally in magnetic-coated tablets. Magnetic-coated tablets, coated with Eudragit® E-100 (E100) and containing 100 mg of metronidazole, were produced. For the in vivo experiments, 12 volunteers participated in the two phases of the study (placebo and omeprazole) on different days to assess the bioavailability of metronidazole. The results indicated a shift as the pH of the solution increased and a delay in the dissolution of metronidazole, showing that the pH increase interferes with the release processes of tablets coated with E100. Our study reinforced the advantages of pharmacomagnetography as a tool to perform a multi-instrumental correlation analysis of the disintegration process and the bioavailability of drugs. Full article
(This article belongs to the Special Issue Dissolution and Disintegration of Oral Solid Dosage Forms)
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26 pages, 7629 KiB  
Article
Modelling and Simulation of the Drug Release from a Solid Dosage Form in the Human Ascending Colon: The Influence of Different Motility Patterns and Fluid Viscosities
by Michael Schütt, Konstantinos Stamatopoulos, Hannah K. Batchelor, Mark J. H. Simmons and Alessio Alexiadis
Pharmaceutics 2021, 13(6), 859; https://doi.org/10.3390/pharmaceutics13060859 - 10 Jun 2021
Cited by 7 | Viewed by 3750
Abstract
For colonic drug delivery, the ascending part of the colon is the most favourable site as it offers the most suitable environmental conditions for drug dissolution. Commonly, the performance of a drug formulation is assessed using standardised dissolution apparatus, which does not replicate [...] Read more.
For colonic drug delivery, the ascending part of the colon is the most favourable site as it offers the most suitable environmental conditions for drug dissolution. Commonly, the performance of a drug formulation is assessed using standardised dissolution apparatus, which does not replicate the hydrodynamics and shear stress evoked by wall motion in the colon. In this work, computer simulations are used to analyse and understand the influence of different biorelevant motility patterns on the disintegration/drug release of a solid dosage form (tablet) under different fluid conditions (viscosities) to mimic the ascending colonic environment. Furthermore, the ability of the motility pattern to distribute the drug in the ascending colon luminal environment is analysed to provide data for a spatiotemporal concentration profile. The motility patterns used are derived from in vivo data representing different motility patterns in the human ascending colon. The applied motility patterns show considerable differences in the drug release rate from the tablet, as well as in the ability to distribute the drug along the colon. The drug dissolution/disintegration process from a solid dosage form is primarily influenced by the hydrodynamic and shear stress it experiences, i.e., a combination of motility pattern and fluid viscosity. Reduced fluid motion leads to a more pronounced influence of diffusion in the tablet dissolution process. The motility pattern that provoked frequent single shear stress peaks seemed to be more effective in achieving a higher drug release rate. The ability to simulate drug release profiles under biorelevant colonic environmental conditions provides valuable feedback to better understand the drug formulation and how this can be optimised to ensure that the drug is present in the desired concentration within the ascending colon. Full article
(This article belongs to the Special Issue Dissolution and Disintegration of Oral Solid Dosage Forms)
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