JP2003508748A - In situ method for measuring release of a substance from a dosage form - Google Patents

Abstract

(57) Abstract: Used to continuously measure the release of a drug from a pharmaceutical dosage form, a single dissolution vessel or a plurality of dissolution vessels (60) containing a dissolution medium and released at a given time A measurement device (50) for detecting the amount of said drug.

Description

Detailed Description of the Invention

CROSS REFERENCE TO RELATED APPLICATIONS This application was filed Aug. 30, 1999 and is entitled US Provisional Patent Application No. 60/151, entitled “In-situ Method for Measuring Release of Substances from Dosage Forms”. No. 443, filed Aug. 21, 1997, claiming priority from U.S. Pat. No. 443, and entitled "Detection System and Method for Predicting Drug Dissolution Curves from Pharmaceutical Dosage Forms." / 915,785, the entire disclosures of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION Dissolution testing is required for all solid oral pharmaceutical dosage forms, where absorption of the drug is necessary for the product to exert its desired therapeutic effect. The United States Pharmacopeia (USP) is one known standard source of information for conducting dissolution and drug release tests in most of the articles for such dosage forms. The exception is for tablets that meet the requirements for solution completion or rapid dissolution (10-15 minutes) of solubility or radiopharmaceutical. Equipment and procedures are based on given requirements and specifications, eg US
P 23rd Edition, Chapter 711 (dissolution), pp. 1791 to 1793. Dissolution testing serves as a quality control, a measure of stability and homogeneity, and as a means of correlating in vitro drug release profiles with in vivo drug release profiles.

Many of the current USP dissolution methods commonly use a temperature programmable water bath maintained at about 37 ° C., where the sample container is submerged in water. These containers include a predetermined amount of dissolution medium and means for agitating the contents within the container. This can be accomplished by a rotating basket mounted on the shaft or a pedal mounted on the shaft, both means being outlined in USP 23rd Edition, Chapter 711 (Dissolution) pp. 1791-1793. . The solid dosage form is placed in a container filled with the medium at time 0 and the specified container temperature and mixing speed are maintained. At regular time intervals (eg 2, 4, 8 hours, etc.), small aliquots of the sample are removed from each vessel, usually by a multi-channel pumping system, each of which is followed by a spectroscopic or high pressure solution chromatograph (HPLC). Shipped in either cuvettes or sample vials for analysis. The plot percentage dissolution of the solid dosage form becomes the dissolution profile over time.

The HPLC method of the above two methods is usually preferred over the spectroscopic method.
However, HPLC lysis offers the advantages of specificity, acceptable accuracy, precision, and sensitivity, but rather has the inherent burden of creating, manipulating, and storing large numbers of sequences and data files, and has a status penalty. . The high cost of HPLC, columns, mobile phases, disposal of waste dissolution media, etc., and the limited number of data points that can be determined make the ideal representation of the release profile of a solid dosage form over time lacking. . Furthermore, HPLC analysis is a sequential time-consuming process. In general, a typical 24-hour dissolution will produce a dissolution profile
Up to 60 hours is required.

Due to the above-mentioned disadvantages of currently available systems, in-situ dissolution methods are needed.

SUMMARY OF THE INVENTION The present invention is a detection system used to continuously measure the release of a drug from a dosage form, comprising a single dissolution vessel or a plurality of dissolution vessels containing a dissolution medium. , A measuring device for detecting the amount of drug released at a given time. Each vessel comprises a mixing shaft disposed therein for mixing the dissolution medium. Probes are placed in the mixing shaft or outside of the individual melting vessels, the probes being UV, I
The dissolution properties can be measured using one or more of R, near IR, fluorescence, electrochemistry, nuclear magnetic resonance (NMR), Raman spectroscopy techniques.

The present invention also relates to a method for predicting the dissolution curve provided by a modified release pharmaceutical dosage form, which comprises removing the drug from the dosage form over a portion of the time the drug is expected to be released. It involves continuously measuring the amount of drug released and predicting the rest of the dissolution curve based on the values obtained.

The present invention relates to an in-situ dissolution method for assessing and learning dissolution properties of drug formulations. Such methods utilize systems that include optical fibers, ultraviolet spectroscopy, fluorescence spectroscopy, NMR and the like.

The present invention specifically relates to detection systems for measuring the dissolution properties of pharmaceutical dosage forms using UV, IR, near IR, Raman spectroscopy techniques, and polarography and NMR.

According to another embodiment of the invention, an improved method for analyzing data from an in-situ dissolution system is provided. According to this embodiment, according to the invention, the sample to be analyzed is placed in a dissolution vessel with a mixing shaft and a probe and the dissolution medium is added to the dissolution vessel. Data from the probe is received and an optical spectrum is generated by the spectrometer at a selected time during the dissolution of the sample in the dissolution medium. First, a baseline correction (eg, via conventional single point baseline correction techniques) is applied to the optical spectrum. Next, the portion of the spectrum corresponding to the absorption of the analyte (eg, a unique component such as an activator) is identified, where this portion extends from the lower wavelength A to the upper wavelength B and at wavelength A , Absorptance W, and absorptance V at wavelength B. Next, the area under the curve (AUC) between wavelengths A and B is calculated. The area of the equilateral triangle (ART) is then calculated, where the equilateral triangle has a hypotenuse defined by a straight line extending from the point (A, W) to the point (B.V). Finally, the area ART is subtracted from the area AUC and the measured peak area (
MPA) is obtained. This MPA is proportional to the amount of drug substance in solution.

According to another embodiment of the present invention, another method for analyzing data from an in-situ dissolution system is provided. According to this embodiment, the sample to be analyzed is placed in a dissolution vessel with a mixing shaft and a probe and the dissolution medium is added to the dissolution vessel. As mentioned above, data from the probe is received and an optical spectrum is generated by the spectrometer at the selected time during the dissolution of the sample in the dissolution medium. However, according to this embodiment, a second order derivative is calculated for the optical spectrum to correct for diffuse interference.

According to another embodiment of the present invention, there is provided a probe including an elongated shaft having an opening formed therein, the probe including a light emitting diode and a photodetector disposed on opposite sides of the opening. It

According to another aspect of this embodiment, there is provided an apparatus for determining the dissolution profile of a pharmaceutical dosage form comprising a releasable amount of a drug active agent, the apparatus immersing the pharmaceutical dosage form in a dissolution medium. And a light-emitting diode and a photodetector arranged on opposite sides of a flow cell arranged in the probe, the probe being arranged in the container and immersed in the dissolution medium. And a processor coupled to the probe. The flow cell is formed as a perforation, hole, or other opening through which the probe penetrates.

According to another aspect of this embodiment, there is provided a method for achieving a specified energy level in a spectrometer, which method comprises: a) detecting from a detector using a first integration time. Capturing data and obtaining a relative energy value as a function; b) comparing the relative energy value with a target relative energy value, and based on the comparison, the integration time as an accepted integration time. Identifying, incrementing the integration time, or decrementing the integration time; c) steps a and b if the allowable integration time is not identified. And a step of repeating.

These and other aspects of the invention will be understood by those of ordinary skill in the art upon reading the detailed description and methods provided by the invention.

Detailed Description of the Preferred Embodiments One aspect of the present invention relates to an improved detection system for continuously measuring the release of a drug from a pharmaceutical dosage form, said detection system comprising a dissolution medium. Consisting of a dissolution vessel containing and a measuring device for detecting the amount of drug released at a given time, said improvement consisting of a mixing shaft containing a probe, said probe being fluorescent, ultraviolet (UV), Infrared (IR), near infrared (NIR), electrochemical and Raman spectroscopy techniques can be used to measure drug release.

The present invention further provides that the probe is an ultraviolet spectroscopic technique, an electrochemical technique, an infrared (IR) technique.
), Near infrared (NIR) or Raman spectroscopy techniques.

Another aspect of the invention is to make a continuous measurement of the amount of drug released from the dosage form over a portion of the time period when the drug is expected to be released and predict the rest of the dissolution curve based on the values obtained. Provided is a method for predicting the dissolution curve provided by a controlled release of a pharmaceutical dosage form.

The method according to the invention utilizes a detection system consisting of a single dissolution vessel or 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 of the detection system consists of a mixing shaft and a probe placed in the mixing shaft or outside the individual dissolution vessels, said probe being UV, IR, near IR, fluorescent, electrochemical. , And Raman spectroscopy techniques can be used to measure dissolution properties.

Yet another aspect of the invention is a drug from a pharmaceutical dosage form comprising a plurality of dissolution vessels containing a dissolution medium and a measurement device for detecting the amount of drug released at a given time. The improvement of the detection system for continuously measuring the release of
The improvement comprises a mixing shaft containing a probe, the probe comprising:
Fluorescent, ultraviolet, infrared, near infrared, electrochemical, and Raman spectroscopy techniques can be used to measure drug release. This aspect of the invention provides that at least two containers can be utilized to optionally hold a dissolution medium or a placebo formulation for baseline correction.

The present invention also provides an improved detection system comprising a single dissolution container or a plurality of dissolution containers containing a dissolution medium and a measurement device for detecting the amount of drug released at a given time. However, the improvement consists of a mixing shaft and a probe placed outside of the individual dissolution vessel, which probe dissolves using UV, IR, near IR, fluorescence, electrochemical, and Raman spectroscopy techniques. Characteristic can be measured. Further, the system of the invention provides that at least two containers optionally hold a dissolution medium or a placebo formulation for baseline correction.

The invention particularly relates to detection systems for measuring the dissolution properties of pharmaceutical dosage forms using ultraviolet, IR, near IR, and Raman spectroscopy techniques and electrochemical techniques such as polarography.

The present invention also relates to a dissolution apparatus for determining the dissolution profile of a pharmaceutical dosage form comprising a releasable amount of a therapeutically active agent, wherein the dosage form comprises a dissolution medium in a container. Submerged in the device, the device includes a detector for quantifying one or more physical / chemical attributes of a therapeutically effective agent, the detector comprising at least a dosage form. Is functionally bound to the dissolution medium for the period of time required to release the maximum releasable amount of the therapeutically active agent; and at least the maximum releasable dose of the dosage form to obtain the dissolution profile of the dosage form. It includes a data processing device for continuously processing the data produced during the period required to release the optically active agent.

The present invention also relates to a method for determining the dissolution profile of a pharmaceutical dosage form comprising a releasable amount of a therapeutically active agent, wherein said dosage form is of a dissolution medium contained in a container. A therapeutically effective agent by immersing the detector in the dosage form and functionally coupling the detector to the dissolution medium for at least the period required to release the maximum releasable amount of the therapeutically effective agent. Continuously generating physical / chemical data specific to the dosage form, and at least during the period required for the dosage form to release the maximum releasable amount of the therapeutically active agent to obtain the dissolution profile of the dosage form. Continuously processing the generated data using a data processing device.

Another preferred embodiment of the present invention relates to a dissolution regimen for measuring the in vitro release of an active agent from a dosage form containing the active agent, the effective agent being measured with the dissolution medium. A fiber optic probe coupled to each of the containers, each of which includes a plurality of containers, each of which includes a dosage form containing, and a detector for simultaneously and continuously measuring the concentration of the effective agent in the dissolution medium, A data processing device connected to the fiber optic probe for continuously processing information regarding the concentration of drug received from the probe to obtain the dissolution profile of the.

In a further preferred embodiment, the dissolution regimen further comprises predicting future concentrations of the active agent while utilizing the data processor.

In another preferred embodiment, the dissolution regimen further comprises utilizing the data processor to predict the total dissolution profile of the active agent after at least 50 percent of the total desired dissolution time frame has elapsed. . For example, the dissolution regimen further includes utilizing the data processor to predict a 24-hour dissolution profile of the active agent after 16 hours of dissolution time have elapsed.

For the purposes of the present invention, the term releasable amount is defined as the maximum amount of therapeutically active agent that can be released from a pharmaceutical dosage form during the dissolution test period. It will be appreciated by the skilled artisan that the releasable amount may be less than 100% of the total amount of agents included in the pharmaceutical dosage form. The dissolution test period is preferably at least 1 hour, and in some embodiments 8 to 24 hours or more, for example 48, 72 or 96 hours.

For the purposes of the present invention, the term physical / chemical attribute means a physical / chemical attribute characteristic of a particular therapeutically effective agent. An unlimited list of physical / chemical attributes includes ultraviolet absorption or emission spectra; infrared absorption or emission spectra; alpha, beta or gamma emission; electronic states; polarities; magnetic resonance; concentration electrochemical attributes and the like. An agent's physical / chemical attributes are those attributes that are available to detect the presence, absence, amount, physical state or chemical state of the agent, for example, that are unique to the agent or population of agents.

For the purposes of the present invention, the term agent is a chemical or physical entity or combination of entities, particles or organisms that can be detected by a detector. A typical list of agents includes drugs, therapeutically effective agents, radioactive particles (eg beta particles); microorganisms such as bacteria, viruses, individual cells of a multicellular organism (eg blood cells) and the like.

For the purposes of the present invention, a detector is defined as a device that detects the physical / chemical attributes of an agent and produces data relating to that physicochemical attribute. Examples of detectors are UV spectrophotometers, Geiger counters, fluoroscopic devices and the like. The physical / chemical attributes detected by the detector and the type of data produced by the detector are not critical to the invention.

For the purposes of the present invention, the term “operatively associated” means that the detector quantifies the desired physical / chemical data specific to the agent and processes that data. It is defined as placing a detector near the container containing the agent of interest so that it can be delivered to the device.

The dissolution apparatus of the present invention is particularly convenient for determining the dissolution profile of a pharmaceutical dosage form containing a releasable amount of a therapeutically active agent, where the dosage form is a dissolution medium in a container. And a device for producing physical / chemical data characteristic of a therapeutically effective agent, said detector comprising at least a dosage form of a maximum releasable amount of the therapeutic agent. Of the therapeutically active agent is functionally bound to the dissolution medium for the time required to release the therapeutically active agent; and at least the dosage form provides a maximum releasable amount of the therapeutically active agent to obtain the dissolution profile of the dosage form. It includes a data processing device that continuously processes the data generated during the time it takes to release.

The detector may be any detector known in the art that produces physical / chemical data of the test agent, such as a UV spectrophotometer. In a preferred embodiment, there is at least one detector for each sample container, ie the detector to sample container ratio is at least 1: 1. In other words, for each sample analyzed, there is a corresponding detector that can continuously produce physical / chemical data characteristics specific to the agent analyzed.

The data processing device may be a device capable of continuously processing the data produced by the detector. In the preferred embodiment, the data processing device is a computer. The data produced by the detector is preferably stored or analyzed by the computer. In a particularly preferred embodiment, the data acquisition device includes data processing software, such as Microsoft Excel 5.0 or Table.
A computer equipped with a curve. The data produced by the detector is processed by the software and reorganized into a preferred form, for example a graph or table. The software preferably processes the data continuously as it is received from the detector.

In an alternative embodiment, the device further comprises a shaft. The shaft has at least one hole therein, which allows the detector to detect the required physical / chemical attribute of the agent of interest and generate the required physical / chemical data. The size and location of the holes along the shaft will depend on a variety of factors including, but not limited to, the type of detector used and the physical / chemical attributes being detected.

In a preferred embodiment, the shaft has a hole therein for receiving the detector. If the shaft is received by the connector, the detector is preferably mounted on the shaft. In a preferred embodiment, the detector is attached to the shaft by known attachment means including, but not limited to, welding, adhesives, solders, screws, friction and the like.

In a preferred embodiment, the detector is permanently attached to the shaft, for example by soldering the detector to the shaft. In another preferred embodiment,
When the detector is received within the shaft, the shaft is free to rotate around the detector, allowing the shaft to perform other functions independently of the detector so that the detector is in a rotatable state. It is attached to the shaft with. For example, a paddle or basket may be attached to at least one end of the shaft so that when the shaft rotates, the paddle or basket also rotates, e.g. agitation when the paddle or basket comes into contact with the external environment, e.g. the dissolution medium. Happens.

In certain preferred embodiments of the invention, the detector measures the concentration of an agent, eg, a therapeutically effective agent, in the medium surrounding the dosage form, eg, simulated gastric fluid or simulated intestinal fluid. By measuring the concentration of the agent in the surrounding medium, the amount of agent released from the dosage form can be calculated. In addition, detectors can be used to measure the amount of multiple agents in the surrounding medium.

The present invention also relates to a method for determining the dissolution profile of a pharmaceutical dosage form containing a releasable amount of a therapeutically active agent, wherein said dosage form is of a dissolution medium contained in a container. A therapeutically effective agent by immersing the detector in the dosage form and functionally coupling the detector to the dissolution medium for at least the period required to release the maximum releasable amount of the therapeutically effective agent. Continuously generating physical / chemical data specific to the dosage form; at least during the period required for the dosage form to release the maximum releasable amount of the therapeutically active agent to obtain the dissolution profile of the dosage form. Continuously processing the generated data using a data processing device.

In a preferred embodiment, the present invention comprises three components: a conventional lysing device, a UV detection unit, and a Pentium® computer running Windows® 95 and Excel 5.0 software. including. A conventional lysing device, the Distek 5100 busless unit (or equivalent unit), is coupled to a UV radiation source by a fiber optic transmission dip probe and further into a series of charge coupled detector (CCD) spectrometers built into the Pentium computer. Be connected. The computer is configured with Windows 95 and Excel 5.0 for system operation and connected to a Novell file server for data storage. Within the Excel software are templates for running the system. A lysing device is used in which the container is rapidly heated by a thin sheath made of electrically resistive material (Distek Premiere 5100 Bathless Unit). A thermocouple inside the shaft of each paddle constantly monitors the temperature of each vessel. The unit uses a container cover engineered to hold the fiber optic probe securely at a predetermined height.

Alternatively, a dissolution apparatus that utilizes an aquarium may be used in place of the bathless unit. The fiber optic dip probe used for transmission is coupled to the deuterium lamp via a fiber with a sheath to provide a UV radiation source for analysis. The dip probe is connected to the CCD spectrometer. The radiation returns from the probe to the CCD spectrometer where it is analyzed and quantified. The inner core of the fiber is preferably UV
It consists of fused silica, which allows efficient propagation of radiation. UV radiation is transmitted from the source lamp through the fiber (into the probe) and through a quartz lens located directly above the flow cell. UV radiation passes through the flow cell and is reflected by a mirror located at the end of the probe. Radiation then travels back through the flow cell and quartz lens. The radiation is guided into a second fiber where it travels toward a spectrometer for analysis. Metering of the drug is accomplished by determining the change in intensity of UV radiation as it passes through the flow cell.

The spectrometer itself consists of a closed light bench mounted on a printed circuit board located in the computer system. The UV radiation entering the spectrometer is propagated through the optical slit, through the mirror and to the grating. The radiation is then reflected from the second mirror towards the charge coupled detector. Each optical fiber probe is a universal SMA
It is connected to each spectrometer using a fixture. CCD spectrometers are calibrated for both wavelength accuracy and quantitative accuracy and precision. A quadratic polynomial is used to determine the wavelength accuracy. This equation compares each wavelength of light striking the CCD to discrete pixels on the array. The control unit consists of a Pentium class computer connected to the Novell network and equipped with several CCD spectrometers, each of which is a Microsoft sheet consisting of multiple sheets.
Full control over Excel 5.0 templates. Excel communicates with the spectrometer via a device driver library. The system parameters are
It can be adjusted by accessing the data acquisition parameters in the Excel worksheet. Parameters for spectrometer control can be set by using either mouse or keystrokes. Applicable information, such as lot number and package type, is entered manually before the test starts. And throughout the lysis, you can access worksheets that present real-time data. As the data is collected, the data is accumulated on the network.

Generally, the agent is dissolved in a solvent, but for the purposes of this invention, the agent can be dispersed or suspended throughout the solvent in a solid or semi-solid medium. Therefore,
For purposes of the present invention, the agent need not be dissolved in the solvent, but may instead provide a dispersing or suspending medium for the agent.

In a preferred embodiment of the invention, the device comprises a detector for monitoring the chemical / physical properties of the agent, wherein the detector comprises a hollow part capable of receiving said detector. Mounted on a carrying shaft, the shaft has a hole therein for allowing the detector to communicate with the external environment when the detector is received by the hollow portion. The detector may be permanently mounted on the shaft or, preferably, may be removably mounted on the shaft to allow for nearly infinite combinations of shaft and detector. To facilitate replacement, the mount is preferably a universal mount that allows for nearly infinite combinations of detector and shaft.

In a preferred embodiment, the detector is specific to a particular agent by a method selected from the group consisting of ultraviolet radiation, infrared radiation, nuclear magnetic resonance, Raman spectroscopy, electrochemical, and mixtures thereof. Data can be obtained and UV radiation detection is particularly preferred.

In a particularly preferred embodiment, the shaft is provided with said detector in order to allow the shaft to rotate freely around the circumference of the detector when it is placed in the hollow part of the shaft. Is rotatably attached to. In this embodiment, the detector may or may not be mounted accordingly, in a manner that allows the detector to rotate independently about an axis in the hollow portion of the shaft.

In another preferred embodiment of the invention, the device comprises data collection means, eg a computer. In a particularly preferred embodiment, the computer is capable of running data collection software that facilitates analysis and collection of the data produced by the detector. For example, the software may just be useful for accumulating data, or it may provide comparative analysis referencing a reference to make a graphical representation of the data (eg, dissolution vs. time curve), or any other variety known in the art. May provide functionality. The software is preferably capable of continuously receiving the data from the detector, providing near-instantaneous access to the data derived from a given test.

In another embodiment of the invention, the detection system further comprises a sampling or dipping manifold for raising and lowering the fiber optic measurement probe to prevent the probe from interfering with the dissolution rate of the dosage form. . In certain embodiments, the tip of the probe is submerged just below the surface of the dissolution medium in the container during dissolution, and down to the USP sampling position in the container just before the dissolution rate analysis of the dosage form begins. Most preferably, the sampling manifold is VanKel.
The 7010 Dissolution Test Station (or equivalent) is an electrified manifold that includes an internal electric part. Other devices or methods known in the art for raising and lowering the probe in a container to test the dissolution rate of a dosage form are also contemplated as within the scope of the present invention.

The present invention is also directed to a method for continuously monitoring an agent in an external environment, such as a dissolution medium, to provide data specific to a particular agent in the external environment. A device for continuously monitoring an agent in a physical environment by placing it at an effective distance from the external environment, said device comprising a hollow portion capable of receiving a detector. A detector for detecting an agent in an external environment mounted on a shaft having a shaft, the shaft having a hole for the detector to communicate with the external environment; Continuously extracting data acquired from the detector during the period of exposure to the physical environment.

It will be appreciated that the electrochemical techniques used in the present invention optionally include a biosensor in which the transducer is coupled to a biological component to measure changes in the concentration of the target analyte.

Examples 1 to 5 Examples 1 to 5 are the in-situ system according to the present invention, a method of creating a real-time dissolution profile with the in-situ system, and a prediction of the dissolution profile with the in-situ system. And various aspects of methods of detecting low dose drugs with the in situ system are described. They should not be construed as limiting the scope of the claims in any way.

The in-situ dissolution system according to the invention has been applied to study the dissolution characteristics of pharmaceutical dosage forms, eg analgesic products such as tramadol hydrochloride QD tablets and hydromorphone capsules.

For Examples 1 to 5, Ocean Optics Inc. PC P
The lug-In Fiber Optic Minute Spectrometer is used with an ultraviolet probe as a detection method. The probe is coupled to the LS-1 deuterium light source and detection is performed using an S1000 spectrometer. Data is Spectr
Process with aScope and Microsoft Excel 5.0 software. The detector is capable of scanning the entire UV and visible spectrum under 2 seconds. A comparison was made with current methods for dissolution analysis of solid dosage forms.

With a more powerful deuterium light source from Oriel Corporation, Stratford, CT, L is used when higher light throughput is required.
The S-1 deuterium lamp can also be replaced. This light source also has the advantage of manipulating the nature of the light hitting the fiber optic interface using a converging lens. The xenon arc lamp source from Oriel Corporation can also be used in applications requiring increased sensitivity such as hydromorphone and hydrocodone controlled release products. In addition, Albuquerque
NM CIC Photonics, Inc. The variable path length dip probe from can be used for method development purposes to determine the optimal flow cell path length for a given drug product.

Fluorescence experiments were performed on a Perkin Elmer model LSS luminescence spectrometer. Excitation spectra were obtained at 220 nm and 500 nm and emission spectra were taken from 300 to 800 nm. The dissolution bath was a Hansen Research model SR5 with Type II (paddle) agitation. Bath temperature 37 + /
Maintained at -0.5 degrees and the solution was stirred at 100 rpm.

Ocean Optics and Microsoft Excel 5.
Spectra Scope software from 0 was used for data collection. Ja
ndel Scientific software (2591 Kerner Bl
Table Carve from vd, San Rafael, CA 94901).
2D and Table Carve 3D were used to generate tabulated data mathematically and predict experimental results.

Example 1 In Situ System Using Ultraviolet-Visible (UV-vis) Spectrometer Figure 1 shows UV-VIS spectra of tramadol standard solutions at four different concentrations. The spectral insights in FIG. 1 reveal relatively noise-free data with well-defined spectral features. The concentrations of tramadol in absorbance versus maximum absorbance (272 nm) are shown in Table 1 below. The correlation coefficient of the regression line is 0.99825, which shows a linear relationship between concentration and absorption. The linearity plot is shown in FIG.

[Table 1] This demonstrates the feasibility of using a fiber optic probe as a spectrometer.

Example 2 Dissolution of tramadol 200 mg QD tablets Three tramadol 200 mg QD tablets were placed in the dissolution media and their release rate was checked by the in situ system over three different days. Repeated UV-vis scans at 30 minute intervals for 25 hours per tablet are shown in FIG.
Shown in. The dissolution data for these tablets are shown in Table 2. Table 2 also shows the dissolution results obtained from the existing validated HPLC method for comparison with three averages.

[Table 2] The table clearly shows that the in situ dissolution system gives results that correlate well with the HPLC method, which was accurate. FIG. 4 shows the average dissolution and HP of three tables.
7 shows a plot of results from the LC method.

Example 3 Dissolution Profile Created in Real Time Tramadol 200 mg QD tablets were placed in an in situ dissolution system,
The amount of tramadol released was monitored in real time. This is Histo
Obtained by a process called ry Channel Evaluation, where a UV-vis scan of the analyte is acquired approximately every 2.5 seconds. The absorption at the preselected wavelength is plotted against time to give the dissolution profile. Figure 5 displays a plot of the dissolution of tramadol tablets over 45 minutes.
This example demonstrates the possibility of applying an in situ system to create a dissolution profile in real time. This is one of the most important applications of the proposed system for immediate release products. This is because the FDA needs such information more and more.

Example 4 Prediction of Dissolution Profile by Curve Fitting Controlled release pharmaceutical dosage forms generally follow a certain release pattern controlled by the physical and chemical properties of the matrix. These release patterns can be predicted mathematically.

For example, using the average dissolution results from Table 1 and using the Table Carve 2D program, the dissolution data can be fitted to the equation as shown in FIG. At the top of Figure 6, the best fit equation for the data is displayed.

If we use the 12 hour data at one hour intervals and fit them to the best fit equation, the dissolution profile created will be that shown in FIG.
When 16-hour data collected at 1-hour intervals was employed to find the best fit equation, it produced the curve of FIG. Note that this curve is closer to the actual experimental data than the one created in Figure 7.

Finally, if we find the best fit curve using the 16 hour data created every half hour, the resulting equation shown in FIG. 9 is exactly 24 hours as shown in FIG. It will be obtained in the experiment.

This example clearly shows that the experiments can be shortened by collecting more frequent data in a short time and mathematical modeling can predict the rest of the results. In-situ systems can also work for this purpose. Because it creates real-time data in real time. Therefore, the predicted result can be given to the prescriber in a shorter time.

Example 5 Detection of Drug Product at Low Dose Strength A dissolution test by conventional spectroscopic methods for low dose strength products such as hydromorphone hydrochloride controlled release 12 mg capsules was performed using the active drug in the dissolution vessel. Would be difficult due to the low concentration of. Using a combination of high intensity lamp and probe tip with relatively long path length (20 mm), a 24 hour dissolution profile is created for 12 mg of hydromorphone hydrochloride comparable to that obtained from the validated HPLC method. . The results are shown in Table 3 and Table 10.

[Table 3] System Design FIG. 11 shows an exemplary system 1 according to an embodiment of the invention.

The system 1 includes a computer 20, a display screen 10, a keyboard 40 and a mouse 30. Multiple (7 in this case) CCDs (charge couples and devices) are coupled to computer 20. In this regard, CCDs (for example,
Isolated external CCD (coupled to computer 20 via PCMIA card)
Can be a spectrometer or a PCB (Printed Circuit Board) in computer 20
Can be an internal CCD spectrometer composed of a closed optics bench mounted in a card slot of An example of an internal CCD spectrometer is the PC Plug-In Fiber Optic Minia manufactured by Ocean Optics.
H produced by a pure spectrometer and Hewlett Packard
Includes a P8452A PDA spectrometer.

As shown in FIG. 11, each of the seven vessels 60 has a fiber optic UV probe 70 and a melting paddle (not shown) disposed therein. Typically, the container 60
One would contain the dissolution medium alone or a placebo formulation in the dissolution medium to provide a baseline spectrum (eg, to be used in the baseline correction calculation). The remaining six containers 60 can hold the sample to be tested. Of course, more or less than seven containers can be placed in the system. A light source 100, such as the LS-1 deuterium light source described above, is coupled to each of the fiber optic UV probes 70. Each UV probe 70 extends from the light source 100 to the container 60 and is coupled at its other end to each CCD spectrometer 50. Preferably, the inner core of the fiber consists of fused silica, which allows UV irradiation to grow well.

FIG. 32 shows a first embodiment of a fiber optic UV probe 70 having a shaft 101, the remote end (not shown) of which is connected to a light source 100 and a CCD spectrometer 50. Shaft 101 contains a pair of fibers (each preferably
Consisting of fused silica). At the proximal end of the shaft 101, the probe 70 includes a detection end 103 that includes a lens for focusing light traveling through the fiber.
Have. Although in the present example cylindrical in shape, the detection end 103 can have any suitable shape as long as it does not interfere with the dissolution to be detected. Figure 3
As shown in FIG. 2, the flow cell 105 is formed as a lumen, an opening, an opening, or a window through end 103. The dissolution medium is free to flow through the flow cell 105 so that dissolution within the medium can be measured.

UV irradiation passes through the first one of the fibers (which extends through the shaft 101 to the probe) and through a quartz lens located directly above the flow cell 105.
Transmitted from the source lamp. The UV radiation travels through the flow cell 105, surface 1
It is reflected by the mirror located at the end of the probe on 09. The illumination is then passed back through the flow cell 105 and the quartz lens back to the second of the fibers, where it travels through the shaft 101 to the analytical spectrometer. Quantitation of the drug substance is accomplished by measuring the change in intensity of UV irradiation as it passes through the flow cell. As explained above, the illumination returns from the fiber optic probe to the CCD spectrometer, where it is analyzed and quantified. Upon entering the spectrometer, the UV radiation is amplified through the optical slit and through the mirror into the grating.
The radiation is then reflected by the second mirror to the charge coupled detector. Each fiber optic probe interfaces with its own spectrometer, preferably using a universal SMA fitting. Calibrate the CCD spectrometer for both wavelength accuracy and quantitative precision and accuracy. A quadratic polynomial is used to measure wavelength accuracy. This equation matches each wavelength of light that hits a CCD with distinct pixels on the array.

The system of FIG. 11 can use open (ie, uncoated) containers, and most preferably utilizes a “closed” (ie, coated) container design as shown in FIG. be able to. An example of a suitable closed container is Dist
It is a k5100 bathless unit. The main advantage of this closed design is to minimize loss of dissolution medium.

In one embodiment of the system of FIG. 11, the probe 70 is inserted into the container 60 for measurement of dissolution and maintained approximately midway between the surface of the dissolution medium and the bottom of the container 60. However, in some applications (such as immediate release tablets), the presence of the probe 70 in the medium may interfere with proper dissolution of the dose in the medium and was taken by the probe 70 located in the container 60. The reading will not accurately reflect the true dissolution rate. However, USP currently requires that the dissolution medium be sampled approximately midway between the surface of the dissolution medium and the bottom of the vessel. Therefore, the system 1 shown in FIG. 11 may alternatively place the dip probe between a first position just below the surface of the dissolution medium and a second position intermediate the surface of the dissolution medium and the bottom of the vessel. A dipping manifold can be used to move to. In this embodiment, the dipping manifold is controlled to automatically dip the probe 70 into the second position immediately before or shortly before taking a reading (eg, every 1, 2, 5 or 10 minutes), The probe can then be raised to the first position when the reading is not being taken. Alternatively, the dipping manifold can be controlled to selectively immerse the probe 70 in the container 60 between the first and second positions (or at any other position relative to the container). Thus, if the operator of the system 1 suspects that there is a turbidity problem, the probe 70 is selectively immersed in (or raised in) the medium to remove the turbulence zone caused by agitation of the paddles in the medium. Can reach external points. An example of a suitable dipping manifold is VanKel 7010 Dis
It is a manifold in the solution Test Station.
However, any other motorized mechanism suitable for moving the dip probe to the first and second positions can be used instead.

In the first example of the probe 70 shown in FIG. 32, the tip 111 of the detection end 103 of the probe 70 is flat and the shaft 101 and the detection end 103 are flat.
Have the same diameter. A potential problem associated with in-situ probes is the bubbles that can form when the probe is inserted into container 60. If these bubbles penetrate the flow cell, they can cause erroneous spectral readings and the measurements obtained may not be accurate. Therefore, in the second specific example of the probe 70 shown in FIG. 33, the tip 1 of the detection end portion 103 of the probe 70 is
12 has a conical shape. The pointed (or conical) end 112 of the probe 70 is intended to reduce bubble formation in the liquid when the probe 70 is first inserted into the liquid in the container 60 for measuring dissolution. In a third embodiment of the probe 70, which is also shown in FIG. 33, the shaft 101 reduces the profile of the probe 70 and the detection end 103 to reduce the hydraulic interference created by the probe in the dissolution medium. Has a smaller diameter than.

In the fourth embodiment of the probe 70 shown in FIG. 34, the detection end 203 of the probe 70 has a flow cell 205 bounding the upper surface 207 and the lower surface 209 of the detection end 203. A single arm 204 is connected to the opposite end,
It is located on the detection end 203 side. This single arm configuration is a flow cell 2
It enhances the flow through 05 and prevents particles from being trapped within the flow cell 205.

33 and 34, the tip 112 of the detection end 203 of the probe 70 is conical or pointed (as in the second embodiment described above) and the shaft 101 (as in the third embodiment). ) It should be noted that although having a reduced profile, the probe according to the third embodiment may instead have a flat detection end 103 (as in the first embodiment) and a uniform profile. . Similarly, the second embodiment need not include the features of the third and fourth embodiments, and the third embodiment need not include the features of the second and fourth embodiments.

FIG. 12 shows a container 60 with a dissolution paddle 90 disposed therein. The design of such a probe has the advantage of not causing flow abnormalities. I mean,
This is because the additional probe need not sink into the dissolution medium. FIG. 13 shows the melting paddle 90 of this embodiment in greater detail. A fiber optic UV probe 70 is shown positioned within the hollow shaft of the melting paddle 90. In addition, a temperature sensor can be placed in the paddle shaft if desired. Alternatively, the temperature sensor can be located elsewhere in the container 60 or eliminated together (in which case the temperature setting of the heating element could be used as an approximation of the temperature of the dissolution bath). As shown in FIG. 12, a window 110 is provided on the shaft to allow the dissolution medium to flow through the shaft, thereby providing optical coupling between the probe and the dissolution medium. A stir motor 120 is also provided for rotation of the melt paddle 90. The agitator motor can be controlled via a computer or in any other known manner. In a simple embodiment, the motor can simply be controlled by a switch.

As mentioned above, the temperature of the melting vessel in the in situ system can be controlled by a water bath, where the vessel is submerged to maintain the proper temperature. Alternatively, as shown in FIG. 12, the melting vessel temperature in the in situ system can be controlled by a bathless arrangement, where each vessel is surrounded by a heating element. This arrangement reduces the size of the equipment and, consequently, bench space and minimizes maintenance. It also allows individual temperature control of each vessel and helps to minimize vibration associated with heat cycling. Suitable heating elements for the bath-free arrangement are Distek, Inc. Commercially available from

In an alternative design to the general embodiment described above, the probe 70 can be located external to the dissolution vessel 60. In such an embodiment, near infrared radiation, which has limited interference from containers such as glass containers, is a good candidate for use in such detection probes. This embodiment avoids the issue of perturbation of the medium potentially interfering with the measurement or the presence of the probe 70 within the medium potentially interfering with the dissolution of the medium.

The present invention can be implemented with detection systems other than those described above.
For example, (1) Glazier, S .; A. Et al, Analytical Lett
ers (1995) 28, 2607-24, the fluorescence described in the publication,
(2) Appl. Phys. Lett. (1993) 63, 1868-70 in Krska, R .; Infrared technology described by (3) Cram, D. et al. J
． And Hammond, G .; S. , Organic Chemistry, M
Other fiber optic systems such as the near infrared and Raman techniques described by cGraw, Hill (1959), which are explicitly incorporated by reference herein and include either a grating or an interferometer system, are also used. be able to. Each of these is a potentially powerful technique, as in dissolution testing. The technique can be used in fiber optic spectrometers similar to that of UV, and these techniques are incorporated into similar in-situ systems for UV detection.

In addition, Differential Pulse Voltametry, C
current Polarograph and Osteryoung S
including the Square Wave Voltametry, Cioer, J. et al. C
． and Hall, E .; A, Journal of Biomedical E
An electrochemical detection system, such as the quantitative electrochemical technique described by N. G., (1988) 10, 210-219, can be applied to monitor analytes dissolved in the dissolution medium. These techniques can be used in situ with different electrode designs such as platinum or glassy electrodes for the evaluation of different products.

In addition, biosensors in which a transducer is attached to a biological element are used to refer to Byerk, D. et al. G. in B
iosensor: Theory and Applications, Tec
Changes in the concentration of the target analyte as described by hnomie Publishing, (1993) can be quantified. The biological element is referred to as the Journal of Chromatograph, which is expressly regarded as part of the present specification.
y (1990) 510, 347-354, where enzymes and antigens / antibodies predominate as selected biological elements, but enzymes or enzyme systems, antigens / antibodies, lectins, Protein, organelle,
It can be a cell or tissue. The biological element is generally cited by Coulct et al. In Journal of Pharm.
acoustic and Biomedical Engineering
(1988) 10, 210-219, immobilized on a support. The transducer can be optic or optical fiber (which measures the most common changes in absorption or luminescence), or electrochemical. Excellent specificity is one of the advantages of biosensors. Such sensors can be used in the in situ system described herein.

Further, non-fiber optic light sources within probe 70 can be used as well.
In such an embodiment, shown in FIG. 35, light is produced by an array of light emitting diodes (LEDs) 310 located on top 307 of flow cell 305. Multiple LEDs, each with a different peak wavelength (eg, between 2 and 10), are preferably placed on top 307 of flow cell 305. Conventional (eg silicon)
A photodiode is located at the bottom 309 of the flow cell 305 to detect the amount of light passing through the flow cell. A "scan" is then obtained by illuminating the medium in the flow cell 305 with each successive diode. The only coupling from the probe 70 is the electrical cable, which includes power, data and control wires. In addition, different types of detectors can be used such as lead sulfide, gallium arsenide (GaAs), gallium (Ga) and indium antimony (InSb).

The use of LEDs as a light source can be applied in dissolution tests, reaction monitoring, general laboratory dissolution analysis, turbidity measurement and pipeline analysis. Currently L
EDs are available in the NIR, UV and visible regions. LED as a light source
The use of is suitable for applications where spectroscopic studies are only required at a limited number of wavelengths, such as quality controlled dissolution tests for pharmaceutical dosage forms. In this respect, the number of wavelengths available in the LED light source is limited by the number of LEDs that can be accommodated in the detector.

Another feature of the invention is a servo system for achieving a constant energy level for all spectrometers used in dissolution tests. In general, servo functions acquire reference spectra at various integration times to achieve a given energy level. Longer integration times will yield larger signals.

As shown in FIG. 36, the servo is controlled by a control module that acquires a reference spectrum at various integration times to achieve a given energy level. First, the servo acquires a reference scan at the lowest predetermined integration time. The servo then acquires the second reference scan at the new integration time. This technique is called Tar
Iteratively iterative until the integration time is selected that yields the desired level of energy called get Percent Relative Energy.

To accurately perform these extrapolations, the servo is such that the intensity response of the spectrometer is relatively linear over a short integration time interval, and the intensity response has the lowest predetermined integration time (eg, 3.6). Assume a monotonic increase over a range of milliseconds) to a maximum predetermined integration time (eg, 6,534.7 milliseconds). As will be seen below, if these assumptions are not valid for a particular spectrometer, the spectrometer is considered non-functional and an error message is generated.

In the following discussion, the minimum predetermined integration time is 3.6 milliseconds (this is the Seis
s spectrometer minimum integration time) and 6,534.76 ms (this is the Sei
The servo function is described in the context of a system which is the maximum integration time of the ss spectrometer.

Two parameters are related to servo function: target percent relative energy and target accuracy. The missing values for these parameters are:
80% and 0.1%. However, other values can be used instead. The servo starts with an integration time of 3.6 ms (the lowest predetermined integration time) by using this value to acquire a data point and then obtaining the relative energy from the spectrometer. The measured relative energies from the last data step are then used to perform a linear extrapolation to determine which new integration time should be used to obtain the target relative energies. The servo has the formula IT _N = IT ^* (TRE / MRE), where IT _N is the new integration time; IT is the integration time; TER is the target relative energy (percent); and MRE is measured. Relative energy (percent)) is used to calculate a new integration time for each subsequent data step.

The servo function will stop whenever the MRE is within target accuracy units from the target percent relative energy. The servo calculates a low limit (target percent relative energy-target accuracy) and a high limit (target percent relative energy + target accuracy). The servo then stops when the measured relative energy is greater than or equal to the low limit and the measured relative energy is less than or equal to the high limit.

For example, using 80% target relative energy and 0.1% target accuracy, if 3
． If a 6 ms integration time resulted in a measured relative energy of 2%, the integration time would need to be increased by approximately 40 times (ie the ratio of the target relative energy to the measured relative energy). , Or 80% / 2%). Therefore, the calculated integration time is 144 ms (ie, 3.6 ms = 4 ms).
0 times). Assuming the spectrometer is perfectly linear, this result provides 80% measured relative energy for an integration time of 144 ms, which causes the servo to move its loop just after two steps. You can stop.

However, this is a rare case, as shown by the table below.
In step 2, the 144 millisecond integration time obtained above results in 90% of the measured relative energy. A ratio of TRE to MRE of 0.89 indicates that the integration time needs to be reduced from 144 ms to 128 ms. Thus, as in step 3, an integration time of 128 msec resulted in a reduced measured relative energy of only 85% and the resulting ratio of TRE to MRE of 0.94 was 120.5 msec. It provides a new integration time which is slightly smaller in seconds.

In step 4, an integration time of 120.5 results in an additional relative energy of 81%, which is still slightly outside the desired limit of 80% ± 0.1%. The resulting ratio of TRE to MRE of 0.99 is 119.
Provide a new integration time of zero. An integration time of 119.0 ms in this example results in exactly 80% relative energy and the interactive process is stopped at step 5.

[Table 4] The data from the reference scans to obtain the target relative energies listed below in Table 4 are plotted in FIG. The plotted line in Figure 37 shows that the spectrometer used is slightly non-linear, but within acceptable limits.

As mentioned above, the system preferably produces an error message if the spectrometer does not perform within the allowed limits for the servo system. One indicator of a non-functional spectrometer is the non-linear intensity response, which is the MRE / MRE
It occurs when p ≦ 0.1 ^* IT _N / IT. The servo system is said to have a relatively linear spectrometer intensity response, such that from one step to the next the increase and / or decrease in relative energy is relatively proportional to the increase and / or decrease in integration time. I assume. A non-linear intensity response occurs when the proportional relative energy increase / decrease is less than 1/10 that of the integration time increase / decrease. If the intensity response is non-linear, the spectrometer is considered non-functional and an error message occurs. Another example of a non-functional spectrometer is caused by the use of extremely high light intensity, which is MRE = 100 and IT = minimum integration time, ie, relative energy equal to 100%, It happens whenever the integration time is equal to the minimum integration time. In addition, non-functional spectrometers can also be caused by high light intensities, MRE ≧ high limit, IT = minimum integration time. That is, it always occurs when the relative energy is greater than the desired high limit and the integration time is the minimum integration time. Similarly, a non-functional spectrometer can be caused by the use of low light intensity, which is MRE <low limit, IT <maximum integration time, that is, relative energy below the desired low limit. So, it happens whenever the integration time is equal to the maximum integration time. If any of these conditions are detected, an error message will result. In response, the user examines the light intensity and, if appropriate, drops (or increases) the light intensity to an acceptable level. In addition, if the servo function performs more than a predetermined maximum number of interactions (e.g. 100) without reaching the target relative energy (+/- target accuracy), an error message will occur.

Spectral Analysis with Scattering Correction As described above, according to embodiments of the present invention, the data received from each probe is analyzed to determine the percentage of active drug that is dissolved over time. This embodiment of the invention will be described with respect to the system of FIG. 11, but other in-situ dissolution systems described herein may be utilized instead.

One of the major obstacles to the development of analytical systems with in situ dissolution monitoring techniques is that the in situ nature of the method precludes sample pretreatment. The standard practice of spectroscopic analysis is to filter the analyte solution prior to optical analysis. The reason for this is simple. Any particulate suspended in the analyte can cause scattering that can interfere with the spectroscopic analysis of the compound under study. However, in-situ lysis techniques inherently prohibit the pretreatment of analytes of this type, thus requiring alternative methods.

The simplest method would be to utilize a single point baseline correction in which the absorbance of a single point is subtracted from the absorbance of the analytical measurement. This works well when the scattering level is small (as in the case of tramadol) compared to the level of analytical absorption. However, in situations where the scattering response is the predominant spectrum, another method is needed.

Tangential Peak Area Spectral Analysis Method In view of the scattering problems described above, there is a need for a mathematical method that selectively analyzes only those areas of the spectrum that result from analyte absorption. One method that achieved this goal is the "floating triangle" method used to quantify hydromorphone hydrochloride in the 12 mg capsules of Example 5 described above. The mathematical basis for this weighing method is depicted in FIG.

Since the height h of the triangle is independent of the slope and height of the baseline b, this measurement can be directly related to the amount of hydromorphone hydrochloride in solution. While this method provides adequate selectivity towards hydromorphone, an improved metering method that is less susceptible to scattering interference is desirable.

By the tangential peak area method according to the invention, the area of the right triangle is subtracted from the total area under the curve of the relevant spectral region. The area of the right triangle, described in more detail below, closely approximates the remaining scatter contribution. FIG. 15 shows how the area under the curve is initially defined by the spectral range of the analyte (260-296 for hydromorphone HCl). Then the baseline subtraction of the curve is applied. The area of the baseline-deducted region is then (from the trapezoidal rule, Stewart, James, calculation method (
Calculus) 2nd edition, p. 455, 1991) Determined by trapezoidal approximation.

The measured peak area (MPA) free of scattering interference is determined by subtracting the area of the right triangle from the total area under the curve, where the right triangle is the point baseline (i) below. , F (i), and the baseline (ii), the base of the triangle is the baseline (i to ii) as shown in FIG.
). In FIG. 16, f (x) intersects the baseline at the higher end of the spectral region (point ii). However, ordinary skill in the art
It will be appreciated that this is merely exemplary and that other spectra may have f (x) baseline values that intersect at the lower end (j) of the spectral region. MPA is proportional to the amount of drug substance in solution.

MPA can be calculated as follows. They are particularly well suited for real-time data generation because the calculations are relatively simple.

1. Baseline measurements are initially in the spectral domain (baseline corrected)
Deducted from every point of.

2. The area under the curve (AUC) is then calculated using the trapezoidal rule of dividing the area under the curve into trapezoids and then calculating the area of the trapezoids. Then AUC
Is defined as the sum of the areas of the individual trapezoids. The area of each trapezoid is equal to , Where A1 is the area of the i ^th interval (trapezoid) and y _ij and y _i are the absorbance values of the specified and past intervals. Therefore, the area under the curve (A
UC) is calculated by the following equation.

[0104] FIG. 15 shows this area under the curve as a shaded area. This area is not corrected for scatter and is not directly used for analytical measurements in this embodiment. In order to correct for scatter, the part of the area containing scatter interference must be deleted. This is achieved by subtracting all but the analytical "ridges" that result from the absorption of our analytes. This can be very closely approximated by removing the area of the right triangle, as shown in FIG. Right triangle (AR
The area of T) is equal to half the height multiplied by the base , The base represents the change in wavelength and the height represents the change in absorbance.

Once both the area under the curve and the area of the right triangle have been determined, the measured peak area (MPA) is defined as the difference between the two:

Measured peak area = AUC-ARP. This measurement can then be used to generate analytical data.

Example 6 To demonstrate how the tangential peak area method calculates more accurately the amount of analyte dissolved, dissolution tests were performed at 12 mg, 16 mg, 24 mn and 32 mn.
Was performed with a hydromorphone capsule.

[0108] Dissolution data is HPLC at 1 hour, 2 hours, 12 hours, 18 hours and 24 hours
Triangular peak sampled every 10 minutes using the method (shown in FIG. 14) in its original position using floating trigonometry and every 10 minutes (shown in FIG. 15). It was obtained in its original position using the area method.

The HPLC data was generated as follows. Melting is 100 RPM, US
It was carried out using the P Device 1 basket method <711>. The dissolution medium was 900 ml of enzyme-free simulated intestinal fluid with 3 grams of sodium chloride added per liter at 37 ° C. The analytes used were 12 mg, 24 mg, and 32 mg capsules of controlled release hydromorphone as described above. Specimens were withdrawn at 1 hour, 2 hours, 12 hours, 18 hours, and 24 hours and analyzed for hydromorphone hydrochloride by HPLC (high pressure liquid chromatography).
Analyzed by The sample was then reversed phase C ₁₈ water Nov at 30 ° C. using a mobile phase of pH 2.9 consisting of sodium dodecyl sulfate, acetonitrile, sodium phosphate monobasic and water.
Separated on a-Pak column. UV absorbance detection at 280 nm was used for quantitative determination.

Data for in situ lysis was obtained using the lysing apparatus of FIG.
Produced using the USP apparatus 2 paddle method at 00 RPM. The dissolution medium is 1
There was 500 ml of simulated intestinal fluid (without enzyme) maintained at 37 ° C. with 3 grams of sodium chloride per liter. The analytes used were 12 mg, 24 mg, and 32 m of controlled release hydromorphone as described above.
g capsules. The melt rating was monitored continuously by a UV fiber optic absorbance dip probe manufactured by Ocean Optics with a path length of 20 mm. The dip probe is shown in FIG.
It was placed in the dissolution vessel adjacent to the mixing axis, as shown in 1. The deuterium light source is Oriel Instruments
Manufactured by Ocean Optics PC1000 Fiber Optic OCD Spectra.
rometer). Absorbance spectra of the dissolution media were created every 10 minutes for a period of 24 hours.

Then, the measured spectra were obtained by the floating trigonometry of FIG. 14, and FIG. 15 and FIG.
6 tangential peak area method. The results of these tests are shown in FIGS. 17-20, demonstrating that the tangential peak area method according to the invention provides results equal to or better than those produced with floating trigonometry.

The most dramatic increase in accuracy is seen for the 12 mg sample (FIG. 17) and the improved floating trigonometry corresponds very well to the HPLC data. This is probably due to the larger number of wavelengths in the tangential peak area method (TRAM) (19 points: 260, 262 ... 296 nm) compared to the floating trigonometry (3 points: 260, 280, 310). It is used, which enhances sensitivity and selectivity. This benefit is most pronounced with the 12 mg capsules, as the 12 mg capsules have a minimal amount of hydromorphone and are therefore more susceptible to inaccuracies flowing from scattering effects.

The data underlying the graphs of FIGS. 17-19 are described below in Tables 5-8.

[Table 5]

[Table 6]

[Table 7]

[Table 8] Second Derivative Spectral Analysis According to embodiments of the present invention, the scattering problem associated with the in situ dissolution method is reduced by calculating the second derivative of the spectrum and subtracting the initial noise offset from the second derivative. To be done. The resulting difference value is then proportional to the amount of analyte dissolved. The second derivative of the UV spectrum of the dissolution bath is first calculated to obtain a plot of dissolved percent active drug versus time.

The derivative of the spectrum at the specified point (i) is the past spectral data point (i−1
) And the slope of a straight line that intersects the next spectral data point (i + 1). As shown in FIG. 21, this line is defined by points (i-1) and (i +
The slope of the line between 1) is almost the same as the tangent line at the spectral data point (i) (parallel)
To approximate the derivative at that point.

Therefore, as shown in FIG. 22, the derivative at any given point in the spectrum can be approximated by calculating the slope between the past data point and the next data point. This slope between the two points is even easier Can be written as

Looking at FIG. 22, the derivative of the point (284 nm) is Calculated by When this calculation is performed for each data point of the spectral plot, the derivative of the spectrum is generated as shown in FIG.

According to the invention, the second derivative of the spectrum is taken to correct the scatter. Since the second derivative represents the rate of change of the rate of change of the function, it will only represent the spectral characteristic in which the peak is present. Lower second derivative using the trapezoidal approximation (
And the area above) can be integrated to produce a value that is characteristic of the amount of analyte in the scattering matrix.

To correct for system noise, the initial noise offset is subtracted from the second derivative plot of the spectral plot. The initial noise offset is set equal to the value of the second derivative at time t = 0, just before the analyte is placed in the dissolution vessel.

Example 7 To demonstrate that the method according to the present invention provides a spectral plot that is not significantly affected by scattering interference, scattering of the pharmaceutical matrix was performed in a spectral observation of dilute tramadol hydrochloride solution. To cause interference,
It was simulated by using a photometric standard (turbidity standard). This experiment was conducted by Hewlett Packard in CC
HP 8452A PDA spectrophotometer manufactured as D (HP 8452A
Was performed using a PDA Spectrophotometer). The spectrophotometer is a card-type CCD that fits into the PCB slot of a computer with a Pentium ^™ processor.

The experiment was performed by scanning the diluted tramadol standard and then adding a small amount of turbidity standard to the sample between scans. The resulting UV spectrum shown in Figure 24 is typical of drug substances when a scattering matrix (polymer) is present.

Tramadol HCL for 0, 1, 2 and 3 drops of turbidity standard respectively
The data described below in Tables 9, 10, 11 and 12 for the turbidity interference results of the analysis of FIG.

[Table 9]

[Table 10]

[Table 11]

[Table 12] The amount of analyte was then quantified using two methods according to the invention, a standard single point baseline correction and a second derivative. The results are summarized in the table below.

[Table 13] The data in Table 13 show that the second derivative method according to the present invention was significantly influenced by how much turbidity standard was added, as evidenced by the very low SD (relative standard deviation). Prove that it provides no value. As one of ordinary skill in the art will appreciate, a low RSD value (ie, standard deviation / mean of values) will result in changes in turbidity
It shows that there is almost no deviation between the measured values. In contrast, the baseline subtraction RSD is rather large, indicating that the turbidity of the solution has a much greater effect on the measured value. In a dynamic matrix environment, it is desirable in this case to accurately quantify the amount of drug dissolved in the analyte that is submerged in the dissolution medium filled with foreign material from the partially dissolved analyte. Is important.

However, it should be noted that the matrix interferences in this experiment are greatly simplified due to the fact that the molecular size of the polymer is uniform. Nevertheless, this test shows that the second derivative method is much less sensitive to turbidity than the traditional baseline subtraction method.

Those of ordinary skill in the art will appreciate that the wide variety of programs known in the art can be used to compute the second derivative or be easily programmed by a computer programmer. In fact, the HP 845 mentioned above
The 2A PDA spectrophotometer includes built-in functionality that could alternatively be used to calculate the first and second derivatives of the acquired spectra.

Example 8 To evaluate the effectiveness of the invention in a real dissolution vessel, the dissolution data obtained by the HPLC method are compared in FIG. 25 with the dissolution data obtained by the invention. The HPLC data are the same data referenced above in connection with Example 6.
The in situ data used was generated in the same way as the data referenced above in connection with Example 6.

HPL at 1 hour, 2 hours, 12 hours, 18 hours and 24 hours as described above.
The dissolution data obtained by the C method is redrawn in FIG. FIG. 25 shows 10
Also shown is a plot of the second derivative of the in situ generated spectrum over the 0 to 24 hour period, sampled every minute. As shown in FIG. 25,
The second derivative function shows the initial offset at t = 0, just before the dose device is added to the container. This initial% dissolution deviation is the result of the integration of the initial noise of the system and is greatly improved by the second derivative result. In the particular example of FIG. 25, the initial value is about 3% at time t = 0.

According to the invention, this initial noise offset (second derivative of the value of the spectrum at t = 0) is subtracted from all future measurements, so that the curve is HPLC
It will correlate well with the sampling data. This corrected second derivative was then used to recalculate both accuracy and precision experiments for the 12 mg and 24 mg hydromorphone HPLC data described above.

FIG. 26 shows an intermediate precision plot for the 12 mg hydromorphone capsules described above. Plots T1 and T2 are plots of dissolution of 12 mg capsules, both described above, performed in situ on the device described above. Effectively, T1 was generated from the same spectral data as the original plot in FIG. However, T1 and T2 are derived from data generated by another technician performing the same measurements on the same device on different days. The data was then processed by floating trigonometry to produce plots T1 and T2.

FIG. 27 also shows an intermediate precision plot for a 12 mg hydromorphone capsule as described above. Plots T1 and T2 were created with the second derivative baseline correction method from the same spectral data as plots T1 and T2, respectively. The plots T1 ′ and T2 ′ were created from the same data as the plots T1 and T2, respectively, so the difference between the plots in FIGS. 26 and 27 is due to the completely different processing method. The comparison of FIGS. 26 and 27 clearly demonstrates that the plot produced by the baseline corrected second derivative method is at least as replicable as the plot of the same data by floating trigonometry.

28 and 29 also show intermediate precision plots of in situ dissolution of the 24 mg hydromorphone capsules described above. Spectral data was generated in the same manner as described above with respect to FIG. As in the case of FIG. 26, FIG.
Plots T3 and T4 are derived from data generated by another technician performing the same measurements on the same device on different days, and the data are floating triangulated to produce plots T3 and T4. It has been processed. Plots T3 ′ and T4 in FIG. 29
'Was generated by the second derivative baseline corrected method from spectral data identical to plots T3 and T4 of FIG. 28, respectively. A comparison of FIGS. 28 and 29 demonstrates that plots made with the baseline corrected second derivative method are at least as replicable as plots of the same data by floating trigonometry.

FIG. 30 shows the HPLC data generated as described in Example 6 in plot T
12 shows a 12 mg accuracy plausibility check comparing 1 (floating trigonometry) and T1 ′ (baseline corrected second derivative method). FIG. 31 likewise shows a 24 mg accuracy plausibility check comparing the HPLC data with plots T3 and T3 ′ of FIGS. 28 and 29, respectively. Both FIG. 30 and FIG. 31 demonstrate that the baseline corrected second derivative method correlates more closely with the HPLC data.

FIGS. 25, 30 and 31 relating to baseline-corrected transfer function plots.
The underlying data for is described below in Tables 14 and 15.

[Table 14]

[Table 15] All of the references identified above are incorporated herein by reference. The examples provided above are not meant to be exclusive. Many other variations of the invention will be readily apparent to those skilled in the art and are intended to be covered by the appended claims.

[Brief description of drawings]

FIG. 1 UV-view (vi) of tramadol standard solution at four different concentrations.
s) shows the spectrum.

FIG. 2 shows a linearity plot of tramadol hydrochloride solution of Example 1.

FIG. 3 is a pictorial representation of a UV-vis scan repeated at 30 minute intervals for 25 hours for the tramadol hydrochloride 200 mg once daily tablet of Example 2.

FIG. 4 shows a plot of the results from the mean dissolution and HPLC method of the three tablets of tramadol hydrochloride in Example 2 once daily.

FIG. 5 shows a plot of dissolution of one tramadol tablet of Example 3 over 45 minutes.

FIG. 6 Ta using the best-fitting equation (as described in Example 4)
By using the ble Curve 2D program, the tramadol controlled releases using the average dissolution results from Table 1 was used.
e) Graph of the dissolution profile of tablets.

FIG. 7 shows the dissolution profile of the tramadol controlled release tablet described in Example 4 obtained from 12 hour sampling data at 1 hour intervals using the best fit equation (as described in FIG. 4). It is a graph.

FIG. 8 is a rough plot showing the dissolution profile of tramadol controlled release tablets taken from 16 hour data taken at 1 hour intervals using the best fit equation (as shown in FIG. 4).

FIG. 9 is a graph of the dissolution profile of tramadol controlled release tablets when 16 hour data generated every 30 minutes is used to find the best fit curve (as shown in FIG. 4).

FIG. 10 shows a plot comparison of dissolution data obtained from both optical fiber and HPLC methods (as shown in Example 6).

FIG. 11 depicts a preferred configuration of the invention.

FIG. 12 depicts an enclosure embodiment of the invention.

FIG. 13 depicts a UV probe in an axial embodiment of the invention.

FIG. 14 illustrates floating trigonometry for determining the area of preselected regions of the spectrum.

FIG. 15 shows a tangential peak area method for determining the area of preselected regions of the spectrum.

16 shows the measured peak area of the tangential peak area method of FIG.

FIG. 17 shows a comparison of dissolution curves of 12 mg controlled release hydromorphone capsules measured by the floating trigonometry, tangential peak area method, and HPLC method.

FIG. 18 shows a comparison of the dissolution curves of 24 mg controlled release hydromorphone capsules measured by the floating trigonometry, tangential peak area method, and HPLC method.

FIG. 19 shows a comparison of the dissolution curves of 16 mg controlled release hydromorphone capsules measured by the floating trigonometry, tangential peak area method, and HPLC method.

FIG. 20 shows a comparison of dissolution curves for 32 mg controlled release hydromorphone capsules measured by the floating trigonometry, tangential peak area method, and HPLC method.

FIG. 21 illustrates a method for obtaining a second derivative of a spectrum according to an embodiment of the invention.

FIG. 22 illustrates a method for obtaining a second derivative of a spectrum according to an embodiment of the invention.

FIG. 23 shows a comparison of UV spectra with its first and second derivatives.

FIG. 24 shows the effect of turbidity interference in the analysis of controlled release tramadol tablets.

FIG. 25: First derivative method, baseline corrected second derivative method, and HP
Figure 3 shows a comparison of dissolution curves of 12 mg controlled release hydromorphone capsules measured by the LC method.

FIG. 26: By comparing the dissolution curves of capsules produced using floating trigonometry from two different experiments performed by two different technicians using the same equipment and method, 12 shows the intermediate precision of 12 mg controlled release hydromorphone capsules.

FIG. 27. Comparing dissolution curves generated using the baseline corrected second derivative method from two different experiments performed by two different technicians using the same apparatus and method. Shows the intermediate accuracy of 12 mg controlled release hydromorphone capsules.

FIG. 28: 24 mg by comparing the dissolution curves of capsules produced using floating trigonometry from two different experiments performed by two different technicians using the same equipment and method. 2 shows the intermediate precision of the controlled release hydromorphone capsules of FIG.

Figure 29: Capsule dissolution curve generated using the baseline corrected second derivative method from two different experiments performed by two different technicians using the same equipment and method, 24 mg. 2 shows the intermediate precision of the controlled release hydromorphone capsules of FIG.

FIG. 30: Floating trigonometry, baseline corrected second derivative method, and HPLC
Figure 3 shows a comparison of dissolution curves of 12 mg controlled release hydromorphone capsules measured by the method.

FIG. 31 Floating trigonometry, baseline corrected second derivative method, and HPLC
Figure 4 shows a comparison of dissolution curves of 24 mg controlled release hydromorphone capsules as measured by the method.

FIG. 32 illustrates an exemplary fiber optic probe according to the first embodiment of the present invention.

FIG. 33 illustrates an exemplary fiber optic probe including features of the second, third and fourth embodiments of the present invention.

FIG. 34 illustrates an exemplary fiber optic probe including features of the second, third and fourth and fifth embodiments of the present invention.

FIG. 35 illustrates a non-fiber optic (LED) probe according to another embodiment of the invention.

FIG. 36 illustrates an exemplary servo function according to embodiments of the invention.

37 is a plot of relative energy versus integration time for an exemplary probe when the servo function of FIG. 36 is performed.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, C A, CH, CN, CR, CU, CZ, DE, DK, DM , DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, K E, KG, KP, KR, KZ, LC, LK, LR, LS , LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, R U, SD, SE, SG, SI, SK, SL, TJ, TM , TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Pocleba, John             United States New York 12603             Povkeepsie Misty Ridge Sir             Curu 9 (72) Inventor Pine, Bud             United States Connecticut 06905             Stamford Bridge Street             197 Apartment 18 F-term (reference) 2G043 AA01 BA16 CA03 DA01 DA08                       EA01 EA03 FA03 FA06 GA25                       GB01 GB21 HA01 HA05 JA01                       KA01 KA02 KA03 KA05 LA03                       NA01 NA02                 2G059 AA01 BB12 CC16 DD01 DD16                       EE01 EE03 EE12 FF07 GG02                       GG03 GG10 HH01 HH02 HH03                       HH06 JJ01 JJ11 JJ17 KK04                       MM01 MM02 MM04

Claims (18)

[Claims] 1. A method for continuously measuring the release of a substance from a pharmaceutical dosage form, comprising: a) placing the pharmaceutical dosage form in a container containing a dissolution medium; and b) determining the spectrum of the dissolution medium. Detecting, c) calculating the second derivative of each detected spectrum, and d) deriving the amount of substance dissolved from the pharmaceutical dosage form from the second derivative. Method. 2. The step (d) comprises the step of subtracting the value of the spectrum from the second derivative immediately before performing the step (a) to obtain a corrected second derivative value. The method of claim 1, wherein the corrected second derivative is proportional to the amount of substance dissolved from the pharmaceutical dosage form. 3. The method of claim 1, wherein the vessel has a mixing shaft disposed therein for mixing the dissolution medium. 4. The method of claim 3, wherein the mixing shaft has paddles disposed thereon. 5. The method of claim 3, wherein step b comprises detecting a spectrum of the dissolution medium utilizing a fiber optic probe located within the mixing shaft. 6. The fiber optic probe is positioned adjacent to a mixing shaft, the mixing shaft being positioned within a vessel for mixing the dissolution medium.
The method according to claim 3. 7. Steps b to d for the second substance in the pharmaceutical dosage form.
The method of claim 1, further comprising repeating. 8. The method of claim 1, further comprising repeating steps b to d multiple times as the dissolution of the dosage form in the dissolution medium progresses. 9. A method for continuously measuring the release of a substance from a dosage, comprising the steps of: a) placing the pharmaceutical dosage form in a container containing a dissolution medium; and b) detecting the spectrum of the dissolution medium. And c) identifying a wavelength range corresponding to the characteristic range of the analyte, said characteristic range extending from x _i to x _n , and the UV spectrum being defined as a function f (x, y). D) generating a baseline correction function f1 (x, y) equal to d) [f (x, y) minus y _i or y _n , whichever is smaller], and e) from x _i to x _n calculating the area under the curve of f1 (x, y), said area under the curve being Defined by the following equation, where delta “x” = abs (x _n −x _i ) in this equation, and f) calculating the region of the lower equilateral triangle (ART), where ART is And g) A. U. C. To obtain the measured peak area MPA of the analyte, said MPA indicating the amount of analyte in the dissolution medium, and h) with respect to the spectra detected at the selected time intervals. Repeating steps b to g to calculate the amount of analyte in the dissolution medium by the end. 10. The method of claim 9, wherein the vessel has a mixing shaft disposed therein for mixing the dissolution medium. 11. The mixing shaft has a paddle disposed thereon,
The method according to claim 10. 12. The method of claim 10, wherein step b comprises detecting a spectrum of the dissolution medium utilizing a fiber optic probe located within the mixing shaft. 13. The method of claim 9, wherein step b comprises utilizing a fiber optic probe disposed within the vessel to detect the spectrum of the dissolution medium. 14. The method of claim 13, wherein the fiber optic probe is positioned adjacent to a mixing shaft, the mixing shaft being positioned within a vessel for mixing the dissolution medium. 15. A device for determining the dissolution profile of a pharmaceutical dosage form comprising a releasable amount of a drug active, said dosage form being immersed in a dissolution medium contained in a container, said device being a dissolution medium. A container for immersing the pharmaceutical dosage form therein, a probe disposed in the container and immersed in the dissolution medium, the probes being disposed on opposite sides of a flow cell formed in the probe. An apparatus comprising: the probe including a light emitting diode and a photodetector; and a processor coupled to the probe. 16. A probe comprising a long shaft having an opening formed therein, the probe including a light emitting diode and a photodetector arranged on opposite sides of the opening. 17. The probe according to claim 16, wherein the opening is a flow cell. 18. A method for achieving a specified energy level on a spectrometer, comprising: a) capturing data from a detector using a first integration time to obtain a relative energy value as a function; b) comparing the relative energy value with a target relative energy value, and based on the comparison, identifying the integration time as an acceptable integration time, incrementing the integration time, and decrementing the integration time. And c) repeating steps a and b if the allowable accumulation time is not identified.