Printer Friendly

Meeting the challenge of controlled release: controlled release tablets have many advantages compared with simpler dosage forms, but their dissolution is hard to adequately monitor using traditional methods. Here, Andy Sowerby, Business Development Director, Oxford Instruments, Molecular Biotools, describes how new, lab-based technology is making 3D imaging and dissolution analysis more accessible to formulation chemists.

According to the USP (United States Pharmacopoeia), a controlled release tablet has its drug release characteristics chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms. Many of today's tablets incorporate controlled release technology because it offers numerous advantages. Tablets that release their contents slowly reduce the frequency with which patients need to remember to take them, thereby improving compliance. Controlled release tablets can also improve bioavailability, and produce more uniform clinical effects and a lower incidence of side effects, as the delivery and release mechanism can be better tailored to the drug involved. Examples are Adalat Oros, REQUIP XL and Lamictal XR.

Unfortunately, most current methods for studying how tablets dissolve and release their contents during drug formulation are not entirely suitable for controlled release tablets, because they are unable to observe how complex composite tablets dissolve in flowing fluid.


Dissolution Testing

Most controlled release tablet dissolution studies involve suspending a tablet in a USP 4 flow cell. The flow cell allows media to pass continuously across the dosage form, and this can be fresh media in an open loop configuration or recycled in a closed loop operation. Samples of the dissolution medium leaving the cell are collected at various time steps and the amount of the active pharmaceutical ingredient present is measured using UV/Visible spectroscopy or high-performance liquid chromatography (HPLC). To date, it has not been possible to observe directly how water enters the tablet causing it to swell or erode in these studies. Instead, this is inferred from the dissolution profile using a model that makes assumptions about, for example, how water diffuses into the tablet and the physical changes that occur.

Although this works with simpler tablet types such as immediate release and solid oral dosage forms, complex controlled release tablets are normally a composite of excipients, including polymers. Conventional gel-matrix tablets, for example, consist of a gel-forming matrix with the drug as the core, surrounded by a water-insoluble layer. As water is absorbed through the coating, the gel matrix swells until it breaks the coating and begins releasing the drug. Such complex behaviours are hard to model accurately as the shape of the dissolution profile is dependent on a number of factors, such as flow rate, ionic concentration and pH, and the assumptions made in the modelling process may not hold.

Invasive Dissolution Studies

Alternatively, to evaluate swelling and or erosion, the dissolution process can be stopped at various times so the tablet can be weighed or cut open. The latter can destroy the tablet completely and potentially introduce other inaccuracies through manual intervention, impacting in experimental reproducibility. This manual intervention (weighing and cutting open) can be slow and laborious. Furthermore, this method does not provide the quality of quantitative data required to compare different controlled release formulations.

Nuclear MRI

Another approach is monitoring the dissolution process optically. An example is the use of terahertz imaging, providing information such as coating thickness, integrity and uniformity. (1) However, these systems are often limited in the data they can provide, e.g. imaging dry tablet characteristics only. The dissolution process can also be observed by placing the tablet in a standard MRI (Magnetic Resonance Imaging) scanner. MRI is a non-destructive technique that utilizes the quantum mechanical properties of certain nuclei including 1H (protons) when placed in a strong static magnetic field. The 1H nuclei are manipulated by the application of a series of radio frequency and magnetic field gradient pulses and the resulting signals are combined and reconstructed to provide a map of the water distribution in up to three dimensions. Acquisition of a series of images during the dissolution period can follow the water ingress into a tablet. Although in conventional scanners this allows the tablet to be imaged, it is difficult to mimic USP 4 conditions of dissolution media flow, past and around the tablet. This means the dissolution process might not adequately reflect what happens in the body, and tests carried out using an MRI scanner do not meet USP 4 standards. Another problem is that conventional MRI equipment is expensive to purchase and operate because, for example, it uses liquid cryogens to cool the superconducting magnet. Furthermore, as these machines are primarily developed for invivo applications, tablet evaluation applications require expert users for pulse programming etc. This means that MRI is not a routine part of the drug formulation development process as time will always need to be booked in advance on a central resource.

New Instrumentation

An instrument has now been developed that provides the advantages of USP 4 apparatus and MRI scanners. The PharmaSense system combines a USP 4 compatible flow cell and MRI scanner into one system so that the controlled release tablet can be imaged while it dissolves in the flow cell and a dissolution profile is collected. Because the system has been developed specifically for formulation, the MRI scanner does not need to be as high resolution as a multipurpose MRI machine and does not require a superconducting magnet. By using a permanent magnet instead, the system is small, lower cost and simple enough to be kept on a bench in every drug formulation laboratory. For the first time, dissolution of composite tablets in a flow cell can be seen almost in real-time, without the need to stop the process and cut open the tablet. In addition, for the first time new information relating to tablet swelling and/or erosion can be determined in a reproducible manner.


The PharmaSense system consists of a 22.6 mm wide flow cell positioned in the active imaging area of the MRI. The tablet is held in a bespoke holder, a wide variety of which are available, optimized to each dosage form. The dissolution media can be pumped through the cell at flow rates of up to 50 mL/min, and the flow circuit can be designed to collect dissolution profiles showing either the increase in the concentration of the drug over time, or the drug release rate. Conventional UV/Vis spectroscopy and pH analysis can be carried out on the flow cell outflow, just like with a traditional USP 4 system. However, at the same time, 2 or 3D images can be collected and displayed on-screen continuously or at fixed time points. For a well-hydrated sample, a 2D image can be displayed typically every two minutes, while a 3D image can take 30 minutes to collect. Collecting UV/Vis spectroscopy, pH and image data simultaneously during dissolution can provide valuable new information to formulation chemists. For example, one could interrogate a formulation that consists of one or more enteric (pH dependent) layers/coatings using a series of media to mimic the pH changes through the gastro-intestinal tract. Thus one can determine the integrity of the layer(s) and hydration kinetics under various conditions in one experiment without having to undergo a series of analyses. Subsequently, those findings can be confirmed by additional analysis of the drug concentration(s) either by on-line UV or fraction collection for offline analysis where appropriate.


Controlled release tablets offer many advantages to patients and are becoming increasingly popular. However, techniques for examining how they dissolve and release their contents have lagged behind these innovations in drug delivery. Now, this is changing, and USP 4 analysis combined with MRI dissolution imaging is poised to become a routine part of formulation development.


(1.) J.A. Zeitler, et al., Terahertz Pulsed Spectroscopy and Imaging in the Pharmaceutical Setting--A Review," J. Pharm. Pharmacol. 59(2), 209-223 (2007).
COPYRIGHT 2008 Via Media Ltd.
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2008 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Title Annotation:solid dosage
Author:Sowerby, Andy
Geographic Code:1USA
Date:Nov 1, 2008
Previous Article:Classic errors, simple solutions: Graham Lampard talks to Richard van Rijnsoever, Director of Business Development and Contracts, SynCo Bio Partners...
Next Article:To sleep: perchance to dream ... Ellen M Martin, from Kureczka/Martin Associates, explores Somnus Therapeutics' investigations into sleep: what it...

Terms of use | Privacy policy | Copyright © 2021 Farlex, Inc. | Feedback | For webmasters