AU729814B2 - Improvements in detection systems and methods for predicting the dissolution curve of a drug from a pharmaceutical dosage form - Google Patents

Description

WO 97/46860 PCT/US97/11791 IMPROVEMENTS IN DETECTION SYSTEMS AND METHODS FOR PREDICTING THE DISSOLUTION CURVE OF A DRUG FROM A PHARMACEUTICAL DOSAGE FORM BACKGROUND OF THE INVENTION Dissolution testing is required for all solid oral pharmaceutical solid dosage form forms in which absorption of the drug is necessary for the product to exert the desired therapeutic effect. The U.S. Pharmacopeia (USP) is one well-known standard source of information which provides for dissolution and drug release testing in the majority of monographs for such dosage forms. Exceptions are for tablets meeting a requirement for completeness of solution or for rapid (10 to minutes) disintegration for soluble or radiolabled drugs. The apparatus and procedure conform to the requirements and specificaitons given, USP 23rd edition Chapter 711 (Dissolution) pages 1791-1793. Dissolution testing serves as a measure of quality control, stability and uniformity as well as a means by which to correlate in-vitro with in-vivo drug release characteristics.

Current USP dissolution methods most commonly employ a temperature programmable water bath, maintained at about 37°C, in which sample vessels are submerged. These vessels contain a predetermined volume of a dissolution media and a means to agitate the contents of the vessel. This may be accomplished by means of a rotating basket attached to a shaft or with a paddle which is also attached to a shaft, both means generally described in USP 23rd edition Chapter 711 (Dissolution) pages 1791-1793. The solid dosage form is placed into the media filled vessel at time zero and specific vessel temperature and mixing speeds are maintained. At fixed time intervals 2, 4, 8 hours, etc.) a small aliquot of sample is taken from each vessel, usually by a multi channeled pumping system, and transported to either a cuvette or a sample vial for subsequent spectrophotometric or high pressure liquid chromatography (HPLC) analysis, respectively. Plotting 2 percentage dissolution of a solid dosage form through time results in a dissolution profile.

Of the two methods discussed above, the HPLC method is usually favoured over the spectrophotometric method. While HPLC dissolution offers the advantage of specificity, acceptable accuracy, precision and sensitivity, the disadvantage of the status quo rather lies with the inherent burden of creating, manipulating, and storing voluminous numbers of sequence and data files. The cost of HPLC, columns, mobile phases, and the waste solvent disposal, etc., is substantial and the limited number of data points that can be determined may result in a less than ideal representation of the release profile of a solid dosage form over time. Furthermore, HPLC analysis is a sequential time consuming in process. In general, a typical 24 hour dissolution requires up to 60 hours to generate a dissolution profile.

Because of the aforementioned disadvantages of currently available systems, an in-situ dissolution method is desirable.

Summary of the Invention i According to one embodiment of this invention there is provided an apparatus for *g determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent wherein the dosage form is immersed in a dissolution medium contained in a vessel, comprising: a vessel for immersinga pharmaceutical dosage form in a dissolution medium; 21 a fiber optic probe disposed within the vessel and immersed in the dissolution medium: a processor coupled to the fiber optic probe, the processor continuously receiving information from the fiber optic probe as the dissolution of the dosage form in the dissolution medium proceeds, the processor analyzing the information and continuously generating a dissolution profile of the dosage form as the dissolution of the dosage form in the dissolution medium proceeds.

According to another embodiment of this invention there is provided an apparatus for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent wherein the dosage form is immersed in a dissolution medium contained in a vessel, comprising: a plurality of vessels for immersing a plurality of pharmaceutical dosage forms in a plurality of dissolution mediums; a plurality of fiber optic probes, each fiber optic probe disposed within a respective -p one of the vessels and immersed in the dissolution medium contained in the respective 5 ne of the vessels; I R:\LIBXX 102486.doc:aak a processor coupled to the fiber optic probe, the processor including a computer coupled to a plurality of UV spectrometers, each fiber optic probe being coupled to a respective one of the UV spectrometers, the processor continuously receiving information from each fiber optic probe as the dissolution of each dosage form in its respective dissolution medium proceeds, the processor analyzing the information and continuously generating a dissolution profile of each dosage form as the dissolution of the dosage form in its respective dissolution medium proceeds.

According to a further embodiment of this invention there is provided a method for determining a dissolution profile of a pharmaceutical dosage form containing a releasable to quantity of a therapeutically active agent wherein the dosage form is immersed in a dissolution medium contained in a vessel, comprising the steps of: immersing a pharmaceutical dosage form in a dissolution medium, the dosage form and the dissolution medium being contained within a vessel; continuously receiving information from a fiber optic probe as dissolution of the iS dosage form in the dissolution medium proceeds, said fiber optic probe disposed within *0 the vessel and immersed in the dissolution media as dissolution of the dosage form in the I dissolution medium proceeds; and analyzing the information and continuously generating a dissolution profile of the dosage form as the dissolution of the dosage form in the dissolution medium proceeds.

According to yet a further embodiment of this invention there is provided an apparatus for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent wherein the dosage form Is immersed in a dissolution medium contained in a vessel, comprising: o"o* a vessel for immersing a pharmaceutical dosage form in a dissolution medium; 25 a mixing shaft disposed within the vessel, the mixing shaft being rotatable for agitating the dissolution medium, the mixing shaft having a fiber optic probe contained within, the fiber optic probe being operatively associated with the dissolution medium; a processor coupled to the fiber optic probe, the processor receiving information lirom the fiber optic probe as the dissolution of the dosage form in the dissolution medium proceeds, the processor analyzing the information and generating a dissolution profile of the dosage form.

Disclosed is an improvement in a detection system used for continuously measuring the release of a drug from a pharmaceutical dosage form comprising a singular dissolution vessel or multiple dissolution vessels containing a dissolution medium and a measuring

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7 C' d evice for detecting the amount of drug released at a given time, the improvement [R:\LI BXX 102486.doc:aak comprising a mixing shaft and a probe placed within the mixing shaft or outside the individual dissolution vessels, the probe capable of measuring the dissolution characteristics using UV, IR, near-lR, fluorescence, electrochemical, nuclear magnetic resonance (NMR), and Raman spectroscopy techniques.

Also disclosed is a method for predicting the dissolution curve provided by a controlled release pharmaceutical dosage form comprising taking continuous measurements of the amount of drug released from a dosage form for a portion of the time over which the drug is expected to be released and predicting the remainder of the dissolution curve based on the values obtained.

in Further disclosed are in-situ dissolution methods to evaluate and study the dissolution characteristics of drug formulations. Such methods utilise systems that include fiber optics, ultraviolet spectroscopy, fluorescence spectroscopy, NMR and the like.

In addition there are disclosed detection systems for measuring dissolution 1 i5 characteristics of pharmaceutical dosage forms using ultraviolet, IR, near-IR, and Raman spectroscopy techniques as well as electrochemical techniques such as polarography, and

NMR.

S*

These and other aspects of the present invention can be followed by one skilled in the art by reading the detailed description and the methods provided by the instant 2 I invention.

Brief Description of the Drawings The following drawings are illustrative of the invention and are not meant to limit the scope of the claims.

S' Figure 1 shows the UY-vis spectra of tramadol standard solutions at four different concentrations: Figure 2 the linearity plot of tramadol I-1CI solutions of Example 1; Figure 3 is a graphical representation of repeated UV-vis scans at 30 minute intervals over 25 hours for a tramadol HCI 2 00mg once-a-day tablet of Example 2; Figure 4 shows the plot of the average dissolution of three tramadol I-CI once-a-day .II tablets of Example 2 and the results from the H-PLC method: Figure 5 displays the plot of the dissolution of a tramadol tablet of Example 3 over minutes: Figure 6 is a graph of the dissolution profile of a tramadol controlled release tablet, uising the average dissolution results from table 1, by using TableCurve 2D program, Ss, i usinsi the best fit equation (as described in Example 4); l R\L 1 B X XX02486,doc:aak Figure 7 is a graph showing the dissolution profile of a tramadol controlled release tablet as described in Example 4 obtained from 12 hour sampling data, at 1 hour intervals, using the to the best fit equation (as described in Example 4); Figure 8 is a graph showing the dissolution profile of a tramadol controlled release Stablet obtained from 16 hour data, taken at 1 hour interval, using the best fitted equation (as described in Example 4); Figure 9 is a graph of a dissolution profile of a tramadol controlled release tablet, when 16 hour data, generated at every half hour, are used to find the best fit curve (as described in Example 4); I, Figure 10 shows a plot comparison of dissolution data obtained from both a fiber optics v. I-IPLC methods (as described in Example 6); Figure 11 depicts a preferred configuration of the present invention; Figure 12 depicts a closed-vessel embodiment of the invention; and Figure 13 depicts a UV probe in shaft embodiment of the invention.

Detailed Description Also disclosed is an improvement in a detection system for continuously measuring *6 the release of a drug from a pharmaceutical dosage form comprising a dissolution vessel containing a dissolution medium and a measuring device for detecting the amount of drug S* released at a given time, the improvement comprising a mixing shaft having a probe 2, contained within, the probe capable of measuring the release of the drug using fluorescence, ultraviolet Infrared near-Infrared electrochemical, and Raman spectroscopy techniques.

*•o In particular, the probe may utilise ultraviolet spectroscopy techniques, electrochemical techniques, Infrared near-Infrared (IR) or Raman spectroscopy Ss techniques.

A-lso disclosed is a method for predicting the dissolution curve provided by a controlled release pharmaceutical dosage form comprising taking continuous measurements of the amount of drug released from a dosage form for a portion of the time over which the drug is expected to be released and predicting the remainder of the 1n dissolution curve based on the values obtained.

A method according to the present invention may utilise a detection system comprising a singular dissolution vessel or multiple dissolution vessels containing a dissolution medium and a measuring device for detecting the amount of drug released at a given time, the improvement in the detection system comprising a mixing shaft and a "probe placed within the mixing shaft or outside the individual dissolution vessels, the IR:\LIBXX]02486.doc:aak 6 probe capable of measuring the dissolution characteristics using UV, IR, near-IR, fluorescence, electrochemical, and Raman spectroscopy techniques.

Also disclosed is a detection system for continuously measuring the release of a drug from a pharmaceutical dosage form comprising a plurality of dissolution vessels containing a dissolution medium and a measuring device for detecting the amount of drug released at a given time, the improvement comprising a mixing shaft having a probe contained within, the probe capable of measuring the release of the drug using 11uorescence, ultraviolet, Infrared, near-Infrared, electrochemical, and Raman spectroscopy techniques.

In The detection system may utilise at least two vessels to optionally hold a dissolution medium or a placebo formulation for baseline correction.

Also disclosed is a detection system for continuously measuring the release of a drug from a pharmaceutical dosage form comprising a singular dissolution vessel or multiple dissolution vessels containing a dissolution medium and a measuring device for detecting the amount of drug released at a given time, the improvement comprising a mixing shaft and a probe placed outside the individual dissolution vessels, the probe capable of measuring the dissolution characteristics using UV, IR, near-IR, fluorescence, o electrochemical, and Raman spectroscopy techniques.

At least two vesselssin the detector system may optionally hold a dissolution medium or a placebo formulation for baseline correction.

The present invention particularly relates to detection systems for measuring Idissolution characteristics of pharmaceutical dosage forms using ultraviolet, IR, near-IR, and Raman spectroscopy techniques as well as electrochemical techniques such as polarography.

2 Further disclosed is a dissolution apparatus for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent wherein the dosage form is immersed in a dissolution medium contained in a vessel, the apparatus including a detector for quantifying one or more physical and/or chemical properties of the therapeutically active agent, the detector operatively associated with the dissolution medium for at least the time period required for the dosage form to release the maximum releasable quantity of therapeutically active agent; and a data processor for continually processing the generated data for at least the time period required for the dosage form to release the maximum releasable quantity of therapeutically active agent to obtain a dissolution profile of the dosage form.

7

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I R:\LIII XX j02486.doc:aak 7 In addition there is disclosed a method for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent wherein the dosage form is immersed in a dissolution medium contained in a vessel, including the steps of continually generating physical and/or chemical data characteristic Sof the therapeutically active agent by operatively associating a detector with the dissolution medium for at least the time period required for the dosage form to release the maximum releasable quantity of therapeutically active agent; and continually processing the generated data with a data processor for at least the time period required for the dosage form to release the maximum releasable quantity of therapeutically active agent to in obtain a dissolution profile of the dosage form.

In one embodiment of the invention there is a dissolution arrangement for measuring in-vilro release of an active agent from a dosage form containing the active agent, including a plurality of vessels, each of the vessels containing a dissolution media and a dosage form containing an active agent to be measured, a fiber optic probe associated with each of the vessels, each of the fiber optic probes including a detector which simultaneously and continuously measures the concentration of active agent in the dissolution media, and a data processor connected to the fiber optic probes, the data processor continually processing information received from the probes concerning the S. concentration of the drug to obtain a dissolution profile of the dosage form.

20 In one particular embodiment, the dissolution arrangement further includes utilising the data processor to predict future concentrations of the active agent. In other preferred embodiments, further include utilising the data processor to predict the entire dissolution profile of the active agent after at least 50 percent of the entire desired dissolution time Iframe has elapsed. For example, the dissolution arrangement further comprises utilising S* 5 the data processor to predict a 24 hour dissolution profile of the active agent after 16 hours of dissolution time has elapsed.

The term releasable quantity is defined, for purposes of the present invention, as the maximum amount of therapeutically active agent that can be released from a pharmaceutical dosage form during the dissolution testing time period. It will be 31, understood by the skilled artisan that the releasable amount may be less than 100% of the total amount of agent contained in the pharmaceutical dosage form. The dissolution testing time period is preferably at least one hour, and in certain embodiments is 8-24 hours or longer, 48, 72 or 96 hours.

I R:\Li BXX]o2486.doc:aak 7a The term physical and/or chemical properties, for purposes of the present invention, is a physical and/or chemical property that is characteristic of a particular therapeutically active agent. A non-limiting list of physical and/or chemical e *0* I R:\I.1BXXJ02486.doc:aak WO 97/46860 PCT/US97/11791 properties include ultraviolet absorption or radiation spectra; infrared absorption or radiation spectra; a, 3 or gamma radiation; electron states; polarity; magnetic resonance; concentration electro-chemical properties and the like. The physical and/or chemical properties of a agent are any property characteristics of a agent or group of agents that can be used to detect, e.g. the presence, absence, quantity, physical state or chemical state of that agent.

For purposes of the present invention, the term agent is defined as any chemical or physical entity or combination of entities, particles or organisms either that are detectable by a detector. An exemplary list of agents include chemicals, therapeutically active agents, radiation particles n-particles); microbes such as bacteria, viruses, individual cells from a multi-cellular organism blood cells); and the like.

A detector is defined for purposes of the present invention as any device that detects a physical and/or chemical property of a agent and generate data regarding about the physio-chemical property. Examples of detectors include UVspectrophotometers, Geiger counters, fluorscopic devices and the like. The physical and/or chemical property detected by the detector and the type of data generated by the detector are not critical to the present invention.

The term "operatively associated" is defined for purposes of the present invention as positioning the detector in proximity to the vessel containing the subject agent such that the detector can quantifyr the desired physical and/or chemical data characteristic of the agent, and transmit the data to a data processor.

DETAILED DESCRIPTION OF THE INVENTION The dissolution apparatus of the present invention is particularly useful for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent wherein the dosage form is immersed in a dissolution medium contained in a vessel, the apparatus including a detector for generating physical and/or chemical data characteristic of the WO 97/46860 PCT/US97/11791 therapeutically active agent, said detector operatively associated with the dissolution medium for at least the time period required for the dosage form to release the maximum releasable quantity of therapeutically active agent; and a data processor for continually processing the generated data for at least the time period required for the dosage form to release the maximum releasable quantity of therapeutically active agent to obtain a dissolution profile of the dosage form.

The detector may be any detector known in the art that generates physical and/or chemical data of the test agent, e.g. a uv spectrophotometer. Preferably, the detector has a probe communicably attached thereto. In preferred embodiments, there is at least one detector per sample vessel; i.e. the ratio of detectors to sample vessels is at least 1:1. In other words, for each sample to be analyzed, there is a corresponding detector capable of continuously generating physical and/or chemical data characteristic of the agent to be analyzed.

The data processor may be any device capable of continuously processing the data generated by the detector. In preferred embodiments, the data processor is a computer. The data generated by the detector is preferably stored and/or analyzed by the computer. In a particularly preferred embodiment, the data collector is a computer that has data processing software, e.g. Microsoft Excel or Tablecurve. The data generated by the detector is processed by the software and reorganized into a preferred form, e.g. as a graph or a table. The data is preferably continuously processed by the software as it is received from the detector.

In an alternative embodiment, the apparatus further comprises a shaft. The shaft has at least one aperature therein, which aperature allows the detector to detect the necessary physical and/or chemical properties of the subject agent and generate the required physical and/or chemical data. The size and position of the opening along the shaft will depend ona variety of factors, including, but not limited to, the type of detector used and the physical and/or chemical property to be detected.

In preferred embodiments, the shaft has an orifice therein for receiving the WO 97/46860 PCT/US97/11791 detector. When the shaft is received by the connector, it is preferable that the detector is attached to the shaft. In preferred embodiments, the detector is attached to the shaft by any attachment means known in the art, including, but not limited to, welds, adhesives, soldering, screws, friction, and the like.

In a preferred embodiment, the detector is permanently attached to the shaft by, for example, soldering the detector to the shaft. In other preferred embodiments, the detector is rotatably attached to the shaft in a manner such that when the detector is receivedin the shaft, the shaft can freely rotate about the detector, allowing the shaft to perform other functions independent of the detector.

For example, a paddle or basket may then be affixed to at least one end of the shaft such when the shaft is rotated, the paddle or basket also rotates to provide, e.g., agitation when the paddle or basket is contacted with an external environment, e.g.

dissolution media.

In certain preferred embodiments of the present.invention, the detector measures the concentration of the agent, therapeutically active agent, in the media surrounding the dosage form, simulated gastic fluid, or simulated intestinal fluid. By measuring the concentration of the agent in the surrounding media, the amount of agent released from the dosage form can be calculated.

The present invention also relates to a method for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent wherein the dosage form is immersed in a dissolution medium contained in a vessel, including the steps of continually generiting physical and/or chemical data characteristic of the therapeutically active agent by operatively associating a detector with the dissolution medium for at least the time period required for the dosage form to release the maximum releasable quantity of therapeutically active agent; and continually processing the generated data with a data processor for at least the time period required for the dosage form to release the maximum releasable quantity of therapeutically active agent to obtain a dissolution profile of the dosage form.

WO 97/46860 PCTIUS971 1791 In a preferred embodiment, the invention includes three components, a conventional dissolution apparatus, a UV detection unit and a Pentium computer running Windows 95 and Excel 5.0 software. The conventional dissolution apparatus, a Distek 5100 bathless unit (or equivalent unit), is interfaced to a UV radiation source with fiber optic transmission dip probes, and a series of charge coupled detector (CCD) spectrometers which are internalized in the Pentium computer. The computer is configured with Windows 95 and Excel 5.0 for operation of the system and connected to a Novell file server for data storage.

Within the Excel software is a template used to run the system. A Dissolution Apparatus is used where vessels are rapidly heated with a thin sheath of electrically resistant material (Distek Premiere 5100 Bathless Unit). A thermocouple present in the shaft of each paddle constantly monitors the temperature of each vessel. The unit uses vessel covers which have been tooled to tightly hold fiber optic probes at specified heights.

Alternatively, a dissolution apparatus utilizing a water bath may be used in place of the bathless unit. A fiber optic dip probe, used for transmission, is interfaced via a sheathed fiber to a deuterium lamp to provide the UV radiation source for the analysis. The dip probe is connected to a CCD spectrometer.

Radiation returns from the probe to the CCD spectrometer where it is analyzed and quantitated. Preferably, the internal core of the fiber consists of fused silica, which allows UV radiation to be efficiently propagated. UV radiation is transmitted from the source Idmp through the fiber (which extends into the probe) and through a quartz lens seated directly above the flow cell. UV radiation travels through the flow cell and is reflected off a mirror positioned at the terminal end of the probe.

The radiation then travels back through the flow cell and quartz lens. It is directed into a second fiber where it travels to the spectrometer for analysis.

Quantitation of the drug substance is accomplished by determining the change in intensity of UV radiation as it is transmitted through the flow cell. The spectrometer itself is comprised of a closed optics bench mounted on a printed WO 97/46860 PCT/US97/11791 circuit board which is situated in the computer system. Upon entering the spectrometer, UV radiation is propagated through an optical slit and onto a grating via a mirror. The radiation is then reflected off a second mirror and onto a charge coupled detector. Each fiber optic probe is interfaced to its own spectrometer using universal SMA fittings.The CCD spectrometer is calibrated for both wavelength accuracy and for quantitative accuracy and precision. A second order polynomial equation is used to determine wavelength accuracy. This equation matches each wavelength of light hitting the CCD with a discrete pixel on the array. The control unit is comprised of a Pentium class computer interfaced to the Novell network and fitted with several CCD spectrometers. The spectrometers are entirely controlled through a Microsoft Excel 5.0 template consisting of multiple sheets. Excel communicates with the spectrometers via a device driver library. The system parameters can be adjusted by accessing the data acquisition parameters within the Excel worksheet. The parameters for spectrometer control can be set by using either the mouse or keystrokes. The applicable information such as lot numbers and package types are manually entered into the spreadsheet before the test begins. A worksheet presenting real-time data can then be accessed throughout the dissolution. As the data is collected it is stored on the network.

Generally, the agent is dissolved in the solvent; however, for purposes of the present invention, the agent may be dispersed or suspended throughout the solvent in a solid or semi-solid media.. Thus, for purposes of the present invention, the agent need not be dissolved in the solvent, but may, instead, provide a dispersion or suspension medium for the agent.

In a preferred embodiment of the invention the device comprises a detector for monitoring chemical and/or physical properties of an agent, wherein the detector is mounted to a shaft having a hollow portion capable of receiving said detection means, said shaft having an aperature therein that allows said detection means to communicate with said external environment when said detection means is received by said hollow portion. The detection means may be permanently mounted WO 97/46860 PCTIUS97/11791 to the shaft, or preferably removably mounted to the shaft to as allow a near infinate combination of shafts and detection means. To facilitate the interchangeabiliy, the mount is preferably a universal mount which will allow an almost infinite combination of detection means and shafts.

In a preferred embodiment, the detection means is capable of aquiring data characteristic of a particular agent by a method selected from the group consisting of ultraviolet radiation, infrared radiation, nuclear magnetic resonance, Raman sprctroscopy, electrochemical, and mixtures thereof, with ultraviolet radiation detection being particularly preferred.

In a particularly preferred embodiment, the shaft is rotatably attached to said detection means, such that the shaft is freely rotatable around the peripheral edges of the detection means when the detection means is situated in the hollow portion of the shaft. In this embodiment, the detection means may or may not be attached in a manner to allow the detection means to independently rotate about an axis within the hollow portion of the shaft, as desired.

In otherpreferred embodiments of the invention, the device includes a data collecting means, e.g. a computer. In particularly preferred embodiments, the computer is capable of operating data collection software which facilitates analysis or collection of the data generated by the detection means. For example, the software may serve to merely store the data, or it may provide compariitive analysis to rfrence standards, produce graphic representations of the data dissolution vs. time curves), or other assorted functions known in the art. The software will preferably be capable of continuously receiving said data from said detection means, providing near-instantaneous access to the data derived from a given test.

The present invention is also directed to a method for continuously monitoring a agent in an external environment, e.g. dissolution media, including the steps of collecting data characteristic to a particular agent in an external environment by positioning at an effective distance to the external environment a device for continually monitoring the agent in the external environment comprising WO 97/46860 PCT/US97/11791 a detection means for detecting a agent in an external environment mounted to a shaft having a hollow portion capable of receiving the detection means; the shaft having an aperature that allows the detection means to communicate with the external environment; and continuously retreiving data obtained from the detection means during the time interval that the device is exposed to the external environment.

It should be understood that the electrochemical techniques used in the present invention optionally include biosensors, in which a transducer is coupled to a biological element, to quantitate a change in concentration of target analyte(s).

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS The following examples illustrate various aspects of the present invention.

They are not to be construed to limit the claims in any manner whatsoever.

I. METHODS I.1 Material The new dissolution system has been applied to study the dissolution characteristics of pharmaceutical dosage forms, for example analgesic products, such as Tramadol HCI QD Tablets and Hydromorphone Capsules.

1.2 Apparatus 1.2.1 Fiber Optics/Ultraviolet Spectroscopy The Ocean Optics Inc. PC Plug-In Fiber Optic Miniature Spectrometer is used with an ultraviolet probe as the method of detection. The probe is coupled to a LS-1 deuterium light source and detection is conducted using a S1000 spectrometer. Data is processed using SpectraScope and Microsoft Excel software. The detector is capable of scanning the entire UV and visible spectrum in under 2 seconds. Comparison with the current method for dissolution analysis of WO 97/46860 PCT/US97/11791 solid dosage forms was conducted.

A more powerful deuterium light source from Oriel Corporation, Stratford, CT can also be used to replace the LS-1 deuterium lamp when higher light throughput is required. This light source also has the advantage of using a condensing lens to manipulate the quality of light hitting the fiber optic interface. A xenon arc lamp source from Oriel Corporation may also be used for applications requiring increased sensitivity, such as Hydromorphone and Hydrocodone Controlled Release Products. In addition, a variable path length dip probe from CIC Photonics, Inc. of Albuquerque NM can be used for method development purposes to determine optimal flow cell pathlength for a given drug product.

1.2.2 Fluorescence Spectroscopy Fluorescence studies were conducted on a Perkin Elmer model Luminescence Spectrometer. The excitation spectrum was obtained from 220 nm to 500 nm and the emission spectrum was taken from 300 to 800 nm.

1.2.3 Dissolution Apparatus The dissolution bath was a Hansen Research model SR5 with type II (paddle) agitation. The bath temperature was maintained at 37 degrees and solution was agitated at 100 rpm.

1.2.4 Software Modules SpectraScope software from Ocean Optics and Microsoft Excel 5.0 was used for data collection. TableCurve 2D and Table curve 3D from Jandel Scientific Software was used to mathematically model tabulated data and predict experimental results. Disclosure generally describing the above software from Jandel Scientific Software is included under Annexure I, and the same is incorporated herein by reference.

WO 97/46860 PCT/US97/11791

EXAMPLES

Example 1 In-situ system using an Ultraviolet-visible spectrometer: Figure 1 shows the UV-vis spectra of Tramadol standard solutions at four different concentrations. Inspection of the spectra in Figure 1 reveals relatively noise free data with well defined spectral features. The absorbance of Tramadol vs.

concentration at the maximum absorbtivity (272 nm) are shown in Table 1 below.

The correlation coefficient of the regression line is 0.999825 indicating a linear relationship between concentration and absorption. The linearity plot is shown in Figure 2.

Table 1. Linearity of Tramadol HCI Tramadol HCI (mg/mL) Absorption at 272 nm 0.0112 0.058 0.0224 0.119 0.0447 0.246 0.112 0.625 0.224 1.211 Correlation Coefficient(r): 0.999825 Slope: 5.4292 y-intercept: 0.001935 This demonstrates the feasibility of using the fiber optical probe as a spectrometer.

WO 97/46860 PCT/US97/11791 Example 2 Dissolution of Tramadol 200 mg QD tablets: Three Tramadol 200 mg QD tablets were placed in the dissolution medium to check its release rate over three different days by the in-situ system. The repeated UV-vis scans at 30 minute intervals over 25 hours for one of the tablets is shown in Figure 3. The dissolution data of these tablets are shown in Table 2.

Table 2 also shows the average of the three and the dissolution results obtained from an existing, validated, HPLC method for comparison.

The table clearly demonstrates that the in-situ dissolution system gives results which are precise and correlate well to the current HPLC method. Figure 4 shows the plot of the average dissolution of three tablets and the results from the HPLC method.

WO 97/46860 WO 9746860PCTIUS97/11791 Table 2 Dissolution of Tramnadol CID 200 mg UV Probe vs. HPLIC 41111998 3W2911995 312011996 Avarage Time thours) Dlssolved:Probe %DissolvedPrb %Dlsealvd:Poabs %Dlssalved:Probe %Dlssolvad:HPLC 0 0 1.8 0.6 NO 1 22.8 15.4 18.2 18.8 21.9 ND 23.3 27.1 25.2 NO 2 27.6 28.6 30.3 29.8 32.2 32.3 33.1 35.3 33.8 ND 3 35.7 37.3 39.4 37.5 NO 39.2 40.1 42.9 40.7 NO 4 42.0 44.0 40.0 44.0 44.7 45.2 46.1 40.7 46.7 NO 47.8 46.7 51.3 49.3 NO 49.7 51.5 53.8 1 51.7 NO 6 52.1 No 52.8 NO 54.1 55.1 58.3 55.8 NO 7 55.9 56.7 60.4 57.7 NO S7.8 56.6 62.0 69.5 NO 8 59.6 60.7 63.7 61.3 60.1 (11.8 61.8 65.4 62.9_ NO 9 62.8 63.5 67.0 64.4 NO 64.8 65.1 66.3 66.1 4O 65.7 66.4 697673a 10.5 66.9 67.6 70.9 68.5 N 1 1 68.5 66.8 72.1 69.8 D 11.5 70.0 70.5 73.3 71.3 NO 12 70.8 72.3 74.4 72.4 71.0 12.5 72.4 72.6 75.7 73.a

NO

13 73.4 74.1F 76.7 74.7

NO

13.5 74.5 75.2 78. 75.9 14U 14 75.6 75.9 79.0 76.8

NO

14.5 76.6 77.4 80.1 76.0

NO

is 77.6 78.5 81.1 79.1

NO

15.5 78.3 79.4 82.2 80.0 ND 16 79.2 79.1 83.1 60.5 ND 16.5 79.9 80.8 64.0 61.6 NO 17 80.8 61.4 64.9 82.4 NO 17.5 61.3 811.8 65.8 82.9 NO i8 51.8 62.6 88.5 83.7 81.8 18.5 82.7 82.8 87.2 64.2 ND 19 83.3 83.9 07.9_ 65.0 NO 19.5 84.0 64.2 8.7 66.6 NO 84.5 84.9 89.4 86.3 NO 20.5 84.9 015.4 90.1 66.8 NO 21 85.9 B6.7 90.3 67.6 NO 21.5 66.2 86.5 91.4 88.0

NO

22 66.4 87.5 -92.0 86.6 NO 22.5 87.4 66.4 92.8 69.5 J NO 23 88.0 86193.3 69.8 NO 24 894 899 94. 91. 9N.

23.5 68.6 8.0 '93.9 _90.5

N

24.5 69.3 89.6 9.913NO 90.3 90.5t95.5 2. NO WO 97/46860 PCT/US97/11791 EXAMPLE 3 Dissolution profiles generated in real time: A Tramadol 200 mg QD tablet was placed in the in-situ dissolution system and the amount of Tramadol released monitored in real time. This was obtained by a process called history channel evaluation in which the UV-vis scans of the analyte are acquired in about every 2.5 seconds. The absorption at a pre-selected wavelength is plotted against time to generate a dissolution profile. Figure displays the plot of the dissolution of Tramadol tablet over 45 minutes. This example illustrates the feasibility of applying the in-situ system to generate the dissolution profile in real time. This is one of the most important applications of the proposed system for immediate release products, because FDA is increasingly requiring for such information.

Example 4 Prediction of the dissolution profile by curve fitting: Controlled-release pharmaceutical dosage forms in general follow certain release patterns controlled by physical and chemical properties of the matrix. These release patterns can be predicted mathematically.

For example, using the average dissolution results from table 1, by using TableCurve 2D program, one can fit the dissolution data into the equation as shown in Figure 6. On top of figure 6, itdisplays the best-fitted equation for the data.

If one uses the 12 hour data, at 1 hour interval, and fits them to the best fit equation the dissolution profile generate would be as the one shown in Figure 7.

When 16 hour data, taken at 1 hour interval, are taken to find the best fitted equation, it produced the curve of Figure 8. Note that this curve is closer so that actual experimental data than that generated in Figure 7.

Finally, when 16 hour data, generated at every half hour, are used to find the best fit curve, the equation produced, as shown in Figure 9, is exactly what one would get in 24 hour experiment, as shown in Figure 6.

WO 97/46860 WO 9746860PCTIUS97/1 1791 This example clearly demonstrates that it is possible to shorten the experiment by taking more frequent data in a short time and predict the remaining results with mathematical modeling. The in-situ system can work to this purpose because it generates instant data in real time. It is therefore able to give a predicted result to formulators in shorter time.

EXAMPLE Detection of drug products with low dosage strength: Dissolution testing by conventional spectroscopic methods for low dosage strength products, such as hydromorphone HCl Controlled Release 12 mg capsules, may be difficult due to low concentrations of active drug in the dissolution vessel.

Using the combination of a high intensity lamp and a probe tip with a relatively long pathlength (20mm), a 24 hour dissolution profile has been generated for hydromorphone HCI 12 mg which is comparable to that obtained from a validated HPLC method. Results are displayed in Table 3 and Figure Table 3. Data of Hydromnorphone HCI 12 mg Capsule Dissolution Fiber Optics v. HPLC 0 Hydromorp vne HCl Dissolved Hour Fiber IHPLC Hourl Fiber HPLC Hour Fiber HPLC Hour IFiber HPLC o 1.7 01 .0.17 2.76 6.171 38.9 12.2 62 18.17 0.33 5.5 6.331 89.2 12.3 62.5 18.33 7.18 6.5 140 12.5 63.2 18.5 79.8 0.67 8.67 6.67 40.6 12.7 63.7 18.67 80.2 0.83 10 6.83 41.5 12.8 64.4 18.83 80.5 1 11.4 111.3 7 42.2 13 64.9 19 80.8 1.17 12.5 7.17 43 13.2 65.5 19.17 81.2 1.33 13.7 7.33, 43.5 13.3 66 19.33 81.6 -1.5 14.8 7.5 144.2 13.5 66.4 82 1.67 16 7.671 44.9 67 ___19.67 1.83 17.2 7.831 45.7 13.8 67.5 19.83 82.6 2 18.1 18.2 8 46.3 56 14 68 20 82.9 2.17 19.3 8.17 46.8 14.2 68.5 20.17 82.9 2.33 20.1 8.33 47.2 69 ___20.33 83.5 21.2 8.5 48.4 14.5 69.6 20.5 183.6 267 21.8 18.67 49.2 14.7 70.2 20.67.206 84 WO 97/46860PC/S7179 PCTIUS97/11791 2.831 22.8 1 831 49.6 14.8 70.7 20.83 84.1 3 23. 9 150.3 15 71.3 21 84.4 3.17 24.7 9.171 51.1 15.2 71.5 21.17 84.6 3.33 25.4 9.331 51.8 15.3 72.1 21.33 84.9 26.1 9.5 52.3 15.5, 72.3 21.5 85.2 3.67 26.9 9.67 53.3 15.7 72.9 21.671 85.4 3.83 28 9.83 53.7 15.8 73.4 21.831 85.5 4 28.7 31.8 10 54.4 16 73.9 22 85.7 4.17 29.7 10.2 55.1 16.2 74.3 22.17 86.2 4.33, 30.5 10.3 55.9 18.3 74.8 22.33 86.3 31.4 10.5 56.2 16.5 75.3 22.5 86.6 4.67 32.2 10.7 57.1 16.7 75.6 22.67 87.1 4.83 32.8 10.8 57.3 16.8 75.8 2.3 87.1 33.7 11 58 17. 76.5 23 87.1 5.17, 34.4 11.21 58.6 17.2 76.9 23.17 87.3 5.33 35.3 11.31 59.1 17.3 77.4 23.33 87.5 36 11.5 59.7 17.5 77.9 23.5 87.7 5.67 36.7 11.7 60.2 17.7 77.9 23.67 87.9 5.83 37.5 11.8 60.9 17.81 784* 23.83, 87.9 6 38.3 12 614 73.8 18 178.9 90.3 24 88.3 99.8_ The present invention generally described below.

can also be practiced using techniques and equipment 11. 1. Detection Systems 11. 1. 1. Other Fiber Optic Systems Fluorescence as described in the publication by Glazier, S. A. et al., Analytical Letters (1995) 28, 2607-24, Infrared techniques as described by Krska, R. et al. in Appl. Phys. Uett. (1993) 63, 1868-70, Near JR and Raman techniques as described by Cram, D.J. and Hammond, Organic Chemistry, McGraw-Hill (1959), all of which are hereby incorporated by reference, either with a grating or interferometer system, are potentially powerful techniques useful for dissolution testing. The techniques can be used with fiber optic spectrometers similar to that of UV. These technologies will be incorporated into the in-situ system similar to that for UV detection.

11.1.2 1.1.2Electrochemical Detection System WO 97/46860 PCT/US97/11791 Quantitative electrochemical techniques as described by Cooper, J.C.

and Hall, Journal of Biomedical Engineering, (1988) 10, 210-219, including Differential Pulse Voltametry, Current Polarography and Osteryoung Square Wave Voltametry can be applied to monitor analytes dissolved in dissolution media.

These techniques will be used in the in-situ system with different electrode designs, such as platinum or glassy carbon electrodes, for evaluation of different products.

11.1.3. Biosensor A biosensor, in which a transducer is coupled to a biological element, can be used to quantitate a change in concentration of target analyte as described by Buerk, D.G. in Biosensors: Theory and Applications, Technomic Publishing, (1993), incorporated herein by reference. The biological element can be an enzyme or enzyme system, antigen/antibody, lectin, protein, organelle, cell, or tissue, though enzymes and antigen/antibodies predominate as biological elements of choice, as described by Lowe et al in Journal of Chromatography (1990) 510, 347-354, incorporated herein by reference. The biological element is generally immobilized on a support as described by Coulet et al in Journal of Pharmaceutical and Biomedical Engineering (1988) 10, 210-219, incorporated herein by reference.

The transducer may be optic or fiber optic (measuring most commonly changes in absorption or luminescence), or electrochemical. Superior specificity is one of the advantages of biosensors. Such sensors will be used in our systems.

11.2. Probe Design 11.2.1 Probe in Shaft A distinct configuration, not having been explored in the present art, is the design of a probe which is totally contained in the mixing shaft of each dissolution vessel. The advantage of this system is the absence of flow aberration, since an additional probe need not be submerged in the dissolution media.

WO 97/46860 PCTIUS97/11791 11.2.2. Probe Outside of Vessel An alternate design to the above places probes outside the dissolution vessels. Near IR which has limited interference from the container, such as glass vessel, is good candidate of such detection probe.

III. Temperature Control The dissolution vessel temperature in the in-situ system can be controlled either by a water bath in which vessels are submerged to maintain appropriate temperature or a bathless configuration, in which each vessel is surrounded by a heating element. The latter configuration reduces the size of the equipment and consequently the bench space, as well as minimizing maintenance. It also allows temperature control of each vessel and also helps to minimize vibration associated with thermocirculation. This is commercially available from Distek, Inc.

IV. System Design With the above configurations, a system is therefore designed as in Figure 11. The figure shows seven vessels in which six can be the samples and one for the dissolution medium itself, or a placebo formula for baseline correction. The actual system, of course, can be any number of vessels in the system.

This system design may be incorporated with a "closed vessel" design as shown in Figure 12. The major advantage of this closed design is to minimize loss of dissolution media. Figure 13 shows a UV probe in shaft embodiment of the present invention.

All of the above-identified references are hereby incorporated by reference.

The examples provided above are not meant to be exclusive. Many other variations of the present invention will be readily apparent to those skilled in the art, and are contemplated to be encompassed within the appended claims.

Claims (14)

1. 2. The apparatus of claim 1, wherein the processor includes a computer and a U V-spectrometer.
2. 5. 3. An apparatus for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent wherein the dosage lform is immersed in a dissolution medium contained in a vessel, comprising: a plurality of vessels for immersing a plurality of pharmaceutical dosage forms in a plurality of dissolution mediums; 2 a plurality of fiber optic probes, each fiber optic probe disposed within a respective one of the vessels and immersed in the dissolution medium contained in the respective one of the vessels; a processor coupled to the fiber optic probe, the processor including a computer coupled to a plurality of UV spectrometers, each fiber optic probe being coupled to a s respective one of the UV spectrometers, the processor continuously receiving information from each liber optic probe as the dissolution of each dosage form in its respective dissolution medium proceeds, the processor analyzing the information and continuously generating a dissolution profile of each dosage form as the dissolution of the dosage form in its respective dissolution medium proceeds. 3. 4. The apparatus of claim 1, further comprising a rotatable mixing shaft disposed within the vessel. The apparatus of claim 1, wherein the fiber optic probe is disposed within the mixing shaft such that the fiber optic probe is operatively associated with the dissolution medium. I R:\LIBXX02486doc:aak
3. 6. The apparatus of claim 1, wherein the processor predicts the dissolution profile of the active agent over a desired dissolution time period, prior to the expiration of the desired dissolution time period and after at least 50 percent of the desired dissolution time period has elapsed.
4. 7. The apparatus of claim 1, wherein the processor predicts a 24 hour dissolution profile of the active agent after 16 hours of dissolution time has elapsed.
5. 8. The apparatus of claim 1, further comprising a display device coupled to the processor, the processor displaying the dissolution profile of the active agent on the display device as a percentage of active agent released versus time. Io 9. The apparatus of claim 1, wherein, prior to a release of a maximum releasable quantity of the active agent from the dosage form, the processor predicts a dissolution profile of the active agent from zero to the maximum releasable quantity. A method for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent wherein the dosage form is immersed in a dissolution medium contained in a vessel, comprising the steps of: immersing a pharmaceutical dosage form in a dissolution medium, the dosage form and the dissolution medium being contained within a vessel; continuously receiving information from a fiber optic probe as dissolution of the dosage form in the dissolution medium proceeds, said fiber optic probe disposed within 2) the vessel and immersed in the dissolution media as dissolution of the dosage form in the dissolution medium proceeds; and analyzing the information and continuously generating a dissolution profile of the dosage form as the dissolution of the dosage form in the dissolution medium proceeds. I 1. The method of claim 10, further comprising the step of displaying the dissolution profile of the active agent on a display device as a 9 percentage of active agent released versus time.
6. 12. The method of claim 10. further comprising the step of predicting a dissolution profile of the active agent over a desired dissolution time period, prior to the expiration of the desired dissolution time period and after at least 50 percent of the desired dissolution time period has elapsed.
7. 13. The method of claim 10, further comprising the step of predicting a 24 hour dissolution profile of the active agent after 16 hours of dissolution time has elapsed.
8. 14. The method of claim 10, further comprising the step of, prior to a release of a maximum releasable quantity of the active agent from the dosage form, predicting a dissolution profile of the active agent from zero to the maximum releasable quantity. [R:\LI BXX]02486.doc:aak 26 An apparatus for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent wherein the dosage lorm is immersed in a dissolution medium contained in a vessel, comprising: a vessel for immersing a pharmaceutical dosage form in a dissolution medium; a mixing shaft disposed within the vessel, the mixing shaft being rotatable for agitating the dissolution medium, the mixing shaft having a fiber optic probe contained within, the fiber optic probe being operatively associated with the dissolution medium; a processor coupled to the fiber optic probe, the processor receiving information from the fiber optic probe as the dissolution of the dosage form in the dissolution medium I0 proceeds, the processor analyzing the information and generating a dissolution profile of the dosage form.
9. 16. The apparatus of claim 15, wherein the mixing shaft has a hollow portion for receiving the fiber optic probe, the mixing shaft further having an aperture formed therein for allowing the fiber optic probe to communicate with the dissolution medium.
10. 17. The apparatus of claim 15, wherein the processor includes a computer and a :I UV-spectrometer. The apparatus of claim 15, wherein the processor continuously receives information from the fiber optic probe as the dissolution of the dosage form in the dissolution medium proceeds, and wherein the processor analyzes the information and 2) continuously generates a dissolution profile of the dosage form as the dissolution of the dosage form in the dissolution medium proceeds.
11. 19. The apparatus of claim 15, wherein the apparatus includes a plurality vessels, each vessel having a respective fiber optic probe disposed therein, and wherein the processor includes a computer coupled to a plurality of UV spectrometers, each fiber 5 optic probe being coupled to a respective one of the UV spectrometers. The apparatus of claim 19, wherein the processor continuously receiving inlormation from the fiber optic probe as the dissolution of the dosage form in the dissolution medium proceeds, the processor analyzing the information and continuously generating a dissolution profile of the dosage form as the dissolution of the dosage form 3, in the dissolution medium proceeds.
12. 21. An apparatus for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent wherein the dosage form is immersed in a dissolution medium contained in a vessel, which apparatus is substantially as herein described with reference to any one of Figs. 11, 12 or 13. I RA:\LI XX 102486.doc:aak 27
13. 22. A method for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent wherein the dosage form is immersed in a dissolution medium contained in a vessel, which method is substantially as herein described with reference to the Examples and the Figures.
14. 23. Apparatus according to any one of claims 1-9, 15-21 when used to determine a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent. Dated 30 November, 2000 Euro-Celtique, S.A. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON $O d 13XX02486.doc:aak