CA2383906A1 - In situ methods for measuring the release of a substance from a dosage form - Google Patents
In situ methods for measuring the release of a substance from a dosage form Download PDFInfo
- Publication number
- CA2383906A1 CA2383906A1 CA002383906A CA2383906A CA2383906A1 CA 2383906 A1 CA2383906 A1 CA 2383906A1 CA 002383906 A CA002383906 A CA 002383906A CA 2383906 A CA2383906 A CA 2383906A CA 2383906 A1 CA2383906 A1 CA 2383906A1
- Authority
- CA
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- Prior art keywords
- dissolution
- probe
- dosage form
- vessel
- dissolution medium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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Classifications
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01J—MEASUREMENT OF INTENSITY, VELOCITY, SPECTRAL CONTENT, POLARISATION, PHASE OR PULSE CHARACTERISTICS OF INFRARED, VISIBLE OR ULTRAVIOLET LIGHT; COLORIMETRY; RADIATION PYROMETRY
- G01J3/00—Spectrometry; Spectrophotometry; Monochromators; Measuring colours
- G01J3/28—Investigating the spectrum
- G01J3/42—Absorption spectrometry; Double beam spectrometry; Flicker spectrometry; Reflection spectrometry
- G01J3/433—Modulation spectrometry; Derivative spectrometry
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/33—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using ultraviolet light
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/84—Systems specially adapted for particular applications
- G01N21/85—Investigating moving fluids or granular solids
- G01N21/8507—Probe photometers, i.e. with optical measuring part dipped into fluid sample
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N13/00—Investigating surface or boundary effects, e.g. wetting power; Investigating diffusion effects; Analysing materials by determining surface, boundary, or diffusion effects
- G01N2013/006—Dissolution of tablets or the like
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/645—Specially adapted constructive features of fluorimeters
- G01N2021/6484—Optical fibres
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/65—Raman scattering
- G01N2021/651—Cuvettes therefore
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/84—Systems specially adapted for particular applications
- G01N21/85—Investigating moving fluids or granular solids
- G01N21/8507—Probe photometers, i.e. with optical measuring part dipped into fluid sample
- G01N2021/8514—Probe photometers, i.e. with optical measuring part dipped into fluid sample with immersed mirror
- G01N2021/8521—Probe photometers, i.e. with optical measuring part dipped into fluid sample with immersed mirror with a combination mirror cell-cuvette
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/84—Systems specially adapted for particular applications
- G01N21/85—Investigating moving fluids or granular solids
- G01N21/8507—Probe photometers, i.e. with optical measuring part dipped into fluid sample
- G01N2021/8528—Immerged light conductor
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/01—Arrangements or apparatus for facilitating the optical investigation
- G01N21/03—Cuvette constructions
- G01N21/05—Flow-through cuvettes
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
- G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
- G01N21/31—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
- G01N21/35—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light
- G01N21/359—Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infrared light using near infrared light
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/65—Raman scattering
Landscapes
- Physics & Mathematics (AREA)
- Spectroscopy & Molecular Physics (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Pharmacology & Pharmacy (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Investigating Or Analysing Materials By Optical Means (AREA)
- Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
Abstract
A detection system used for continuously measuring the release of a drug fro m a pharmaceutical dosage form comprising a singular dissolution vessel or multiple dissolution vessels (60) containing a dissolution medium and a measuring device (50) for detecting the amount of drug released at a given time is provided.
Description
IN SITU METHODS FOR MEASURING THE RELEASE
OF A SUBSTANCE FROM A DOSAGE FORM
Cross-Reference to Related Applications This application claims priority from United States Provisional Patent Application Number 60/151,443, filed August 30, 1999 and entitled "In Situ Methods For Measuring The Release Of A Substance From A Dosage Form" and is related to pending United Stated Patent Application Number 08/915,785, filed August 21, 1997 and entitled "Detection Systems and Methods for Predicting the Dissolution Curve of a Drug from a Pharmaceutical Dosage Form,"
the entire disclosures of which are hereby incorporated by reference.
Background of the Invention Dissolution testing is required for all solid oral pharmaceutical dosage forms in which absorption of the drug is necessary in order for the product to exert the desired therapeutic effect.
The U.S. Pharmacopoeia (USP) is one well-known standard source of information that 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 15 minutes) disintegration of soluble or radiolabled drugs. The apparatus and procedure conform to the requirements and specifications given, e.g., 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 that 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 (e.g. 2, 4, 8 hours, etc.) a small aliquot of sample is taken from each vessel, usually by a mufti 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 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 favored over the spectrophotometric method. However, 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 an ideal representation of the release profile of a solid dosage form over time.
Furthermore, HPLC analysis is a sequential time consuming process. In general, a typical 24-hour dissolution requires up to 60 hours in order 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 The present invention relates to 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 device for detecting the amount of drug released at a given time.
Each vessel has a mixing shaft disposed therein for mixing the dissolution medium. A probe placed within the mixing shaft or outside the individual dissolution vessels, the probe capable of measuring the dissolution characteristics using one or more of UV, IR, near-IR, fluorescence, electrochemical, nuclear magnetic resonance (NMR), and Raman spectroscopy techniques.
The present invention also relates to 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.
The present invention relates to in-situ dissolution methods to evaluate and study the dissolution characteristics of drug formulations. Such methods utilize systems that include fiber optics, ultraviolet spectroscopy, fluorescence spectroscopy, NMR and the like.
The present invention specifically relates to detection systems for measuring dissolution characteristics of pharmaceutical dosage forms using ultraviolet, IR, near-IR, and Raman spectroscopy techniques as well as electrochemical techniques such as polarography, and NMR.
In accordance with another embodiment of the present invention, an improved method of analyzing data from an in-situ dissolution system is provided. In accordance with this embodiment, a sample to be analyzed is placed in a dissolution vessel having a mixing shaft and probe in accordance with the present invention, and a dissolution media is added to the dissolution vessel. Data from the probe is received and an optical spectrum is generated by a spectrometer at selected times during the dissolution of the sample in the dissolution media.
First a baseline correction (e.g. via a conventional single point baseline correction technique) is applied to the optical spectrum. A portion of the spectrum corresponding to the absorption of the analyte (e.g., a component of interest such as an active agent) is then identified, wherein the portion extends from a lower wavelength A, to an upper wavelength B, with an absorbance W at wavelength A, and an absorbance V at wavelength B. The area under the curve (AUC) between wavelength A and B is then calculated. An area of a right triangle (ART) is then calculated, wherein the right triangle has a hypotenuse defined by a straight line extending from point (A, W) to (B, V). Finally, the area ART is subtracted from the area AUC to obtain a measured peak area (MPA). The MPA is proportional to the amount of drug substance in solution.
In accordance with yet another embodiment of the invention, another method of analyzing data from an in-situ dissolution system is provided. In accordance with this embodiment, a sample to be analyzed is placed in a dissolution vessel having a mixing shaft and probe in accordance with the present invention, and a dissolution media is added to the WD ~l/16582 CA 02383906 2002-02-27 PC1,/~$~~n38~~
dissolution vessel. Data from the probe is received and an optical spectrum is generated by a spectrometer at selected times during the dissolution of the sample in the dissolution media as set forth above. In accordance with this embodiment, however, a second order derivative is calculated for the optical spectrum in order to correct for scattering interference.
In accordance with another embodiment of the present invention, a probe is provided which includes an elongated shaft having an opening formed therein, the probe including a light emitting diode and a photodetector disposed on opposing sides of the opening.
In accordance with a further aspect of this embodiment, an apparatus for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent is provided which includes a vessel for immersing a pharmaceutical dosage form in a dissolution medium; a probe disposed within the vessel and immersed in the dissolution medium, the probe including a light emitting diode and a photodetector disposed on opposing sides of a flow cell formed in the probe; and a processor coupled to the probe. The flow cell is formed as a bore, aperture, or other opening through the probe.
In accordance with another embodiment of the present invention, a method for achieving a specified energy level on a spectrometer is provided which includes the steps of a) acquiring data from a detector using a first integration time and obtaining a relative energy value as a function thereof; b) comparing the relative energy value with a target relative energy value and, based upon said comparison, either identifying the integration time as an accepted integration time, incrementing the integration time, or decrementing the integration time;
and c) repeating steps a and b if the accepted integration time has not been identified.
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 invention.
Brief Description of the Drawings Fig. 1 shows the UV-vis spectra of tramadol standard solutions at four different concentrations;
OF A SUBSTANCE FROM A DOSAGE FORM
Cross-Reference to Related Applications This application claims priority from United States Provisional Patent Application Number 60/151,443, filed August 30, 1999 and entitled "In Situ Methods For Measuring The Release Of A Substance From A Dosage Form" and is related to pending United Stated Patent Application Number 08/915,785, filed August 21, 1997 and entitled "Detection Systems and Methods for Predicting the Dissolution Curve of a Drug from a Pharmaceutical Dosage Form,"
the entire disclosures of which are hereby incorporated by reference.
Background of the Invention Dissolution testing is required for all solid oral pharmaceutical dosage forms in which absorption of the drug is necessary in order for the product to exert the desired therapeutic effect.
The U.S. Pharmacopoeia (USP) is one well-known standard source of information that 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 15 minutes) disintegration of soluble or radiolabled drugs. The apparatus and procedure conform to the requirements and specifications given, e.g., 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 that 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 (e.g. 2, 4, 8 hours, etc.) a small aliquot of sample is taken from each vessel, usually by a mufti 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 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 favored over the spectrophotometric method. However, 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 an ideal representation of the release profile of a solid dosage form over time.
Furthermore, HPLC analysis is a sequential time consuming process. In general, a typical 24-hour dissolution requires up to 60 hours in order 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 The present invention relates to 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 device for detecting the amount of drug released at a given time.
Each vessel has a mixing shaft disposed therein for mixing the dissolution medium. A probe placed within the mixing shaft or outside the individual dissolution vessels, the probe capable of measuring the dissolution characteristics using one or more of UV, IR, near-IR, fluorescence, electrochemical, nuclear magnetic resonance (NMR), and Raman spectroscopy techniques.
The present invention also relates to 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.
The present invention relates to in-situ dissolution methods to evaluate and study the dissolution characteristics of drug formulations. Such methods utilize systems that include fiber optics, ultraviolet spectroscopy, fluorescence spectroscopy, NMR and the like.
The present invention specifically relates to detection systems for measuring dissolution characteristics of pharmaceutical dosage forms using ultraviolet, IR, near-IR, and Raman spectroscopy techniques as well as electrochemical techniques such as polarography, and NMR.
In accordance with another embodiment of the present invention, an improved method of analyzing data from an in-situ dissolution system is provided. In accordance with this embodiment, a sample to be analyzed is placed in a dissolution vessel having a mixing shaft and probe in accordance with the present invention, and a dissolution media is added to the dissolution vessel. Data from the probe is received and an optical spectrum is generated by a spectrometer at selected times during the dissolution of the sample in the dissolution media.
First a baseline correction (e.g. via a conventional single point baseline correction technique) is applied to the optical spectrum. A portion of the spectrum corresponding to the absorption of the analyte (e.g., a component of interest such as an active agent) is then identified, wherein the portion extends from a lower wavelength A, to an upper wavelength B, with an absorbance W at wavelength A, and an absorbance V at wavelength B. The area under the curve (AUC) between wavelength A and B is then calculated. An area of a right triangle (ART) is then calculated, wherein the right triangle has a hypotenuse defined by a straight line extending from point (A, W) to (B, V). Finally, the area ART is subtracted from the area AUC to obtain a measured peak area (MPA). The MPA is proportional to the amount of drug substance in solution.
In accordance with yet another embodiment of the invention, another method of analyzing data from an in-situ dissolution system is provided. In accordance with this embodiment, a sample to be analyzed is placed in a dissolution vessel having a mixing shaft and probe in accordance with the present invention, and a dissolution media is added to the WD ~l/16582 CA 02383906 2002-02-27 PC1,/~$~~n38~~
dissolution vessel. Data from the probe is received and an optical spectrum is generated by a spectrometer at selected times during the dissolution of the sample in the dissolution media as set forth above. In accordance with this embodiment, however, a second order derivative is calculated for the optical spectrum in order to correct for scattering interference.
In accordance with another embodiment of the present invention, a probe is provided which includes an elongated shaft having an opening formed therein, the probe including a light emitting diode and a photodetector disposed on opposing sides of the opening.
In accordance with a further aspect of this embodiment, an apparatus for determining a dissolution profile of a pharmaceutical dosage form containing a releasable quantity of a therapeutically active agent is provided which includes a vessel for immersing a pharmaceutical dosage form in a dissolution medium; a probe disposed within the vessel and immersed in the dissolution medium, the probe including a light emitting diode and a photodetector disposed on opposing sides of a flow cell formed in the probe; and a processor coupled to the probe. The flow cell is formed as a bore, aperture, or other opening through the probe.
In accordance with another embodiment of the present invention, a method for achieving a specified energy level on a spectrometer is provided which includes the steps of a) acquiring data from a detector using a first integration time and obtaining a relative energy value as a function thereof; b) comparing the relative energy value with a target relative energy value and, based upon said comparison, either identifying the integration time as an accepted integration time, incrementing the integration time, or decrementing the integration time;
and c) repeating steps a and b if the accepted integration time has not been identified.
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 invention.
Brief Description of the Drawings Fig. 1 shows the UV-vis spectra of tramadol standard solutions at four different concentrations;
Fig. 2 shows the linearity plot of tramadol HCl solutions of Example 1;
Fig. 3 is a graphical representation of repeated LTV-vis scans at 30-minute intervals over 25 hours for a tramadol HCl 200mg once-a-day tablet of Example 2;
Fig. 4 shows a plot of the average dissolution of three tramadol HCl once-a-day tablets of Example 2 and the results from the HPLC method;
Fig. 5 shows a plot of the dissolution of a tramadol tablet of Example 3 over 45 minutes;
Fig. 6 is a graph of the dissolution profile of a tramadol controlled release tablet, using the average dissolution results from table 1, by using TableCurve 2D program, using the best fit equation (as described in Example 4);
Fig. 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 best fit equation (as described in Example 4);
Fig. 8 is a graph showing the dissolution profile of a tramadol controlled release tablet obtained from 16 hour data, taken at 1 hour intervals, using the best fitted equation (as described in Example 4);
Fig. 9 is a graph of a dissolution profile of a tramadol controlled release tablet, when 16 hour data generated at every half hour is used to find the best fit curve (described in Example 4);
Fig. 10 shows a plot comparison of dissolution data obtained from both a fiber optics v.
HPLC methods (as described in Example 6);
Fig. 11 depicts a preferred configuration of the present invention;
Fig. 3 is a graphical representation of repeated LTV-vis scans at 30-minute intervals over 25 hours for a tramadol HCl 200mg once-a-day tablet of Example 2;
Fig. 4 shows a plot of the average dissolution of three tramadol HCl once-a-day tablets of Example 2 and the results from the HPLC method;
Fig. 5 shows a plot of the dissolution of a tramadol tablet of Example 3 over 45 minutes;
Fig. 6 is a graph of the dissolution profile of a tramadol controlled release tablet, using the average dissolution results from table 1, by using TableCurve 2D program, using the best fit equation (as described in Example 4);
Fig. 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 best fit equation (as described in Example 4);
Fig. 8 is a graph showing the dissolution profile of a tramadol controlled release tablet obtained from 16 hour data, taken at 1 hour intervals, using the best fitted equation (as described in Example 4);
Fig. 9 is a graph of a dissolution profile of a tramadol controlled release tablet, when 16 hour data generated at every half hour is used to find the best fit curve (described in Example 4);
Fig. 10 shows a plot comparison of dissolution data obtained from both a fiber optics v.
HPLC methods (as described in Example 6);
Fig. 11 depicts a preferred configuration of the present invention;
Fig. 12 depicts a closed-vessel embodiment of the invention;
Fig. 13 depicts a W probe in shaft embodiment of the invention;
Fig. 14 illustrates a floating triangle method for determining the area of pre-selected region of a spectrum;
Fig. 15 illustrates a tangential peak area method for determining the area of a pre-selected region of a spectrum;
Fig. 16 shows a measured peak area of the tangential peak area method of Figure 15;
Fig. 17 shows a comparison of a dissolution curve for a 12 mg controlled release hydromorphone capsule measured by the floating triangle method, the tangential peak area method, and an HPLC method;
Fig. 18 shows a comparison of a dissolution curve for a 24 mg controlled release hydromorphone capsule measured by the floating triangle method, the tangential peak area method, and an HPLC method;
Fig. 19 shows a comparison of a dissolution curve for a 16 mg controlled release hydromorphone capsule measured by the floating triangle method, the tangential peak area method, and an HPLC method;
Fig. 20 shows a comparison of a dissolution curve for a 32 mg controlled release hydromorphone capsule measured by the floating triangle method, the tangential peak area method, and an HPLC method;
Figs. 21 and 22 illustrate a method for obtaining a second derivative of a spectra in accordance with an embodiment of the present invention;
Fig. 13 depicts a W probe in shaft embodiment of the invention;
Fig. 14 illustrates a floating triangle method for determining the area of pre-selected region of a spectrum;
Fig. 15 illustrates a tangential peak area method for determining the area of a pre-selected region of a spectrum;
Fig. 16 shows a measured peak area of the tangential peak area method of Figure 15;
Fig. 17 shows a comparison of a dissolution curve for a 12 mg controlled release hydromorphone capsule measured by the floating triangle method, the tangential peak area method, and an HPLC method;
Fig. 18 shows a comparison of a dissolution curve for a 24 mg controlled release hydromorphone capsule measured by the floating triangle method, the tangential peak area method, and an HPLC method;
Fig. 19 shows a comparison of a dissolution curve for a 16 mg controlled release hydromorphone capsule measured by the floating triangle method, the tangential peak area method, and an HPLC method;
Fig. 20 shows a comparison of a dissolution curve for a 32 mg controlled release hydromorphone capsule measured by the floating triangle method, the tangential peak area method, and an HPLC method;
Figs. 21 and 22 illustrate a method for obtaining a second derivative of a spectra in accordance with an embodiment of the present invention;
Fig. 23 shows a comparison of a W spectra with its first and second derivatives;
Fig. 24 illustrates the influence of turbidity interference in the analysis of a controlled release tramadol tablet;
Fig. 25 shows a comparison of a dissolution curve for a 12 mg controlled release hydromorphone capsule measured by a second derivative method, a baseline corrected second derivative method, and an HPLC method;
Fig. 26 illustrates the intermediate precision of a 12 mg controlled release hydromorphone capsule by comparing dissolution curves for a capsule generated using the floating triangle method from two different experiments conducted by two different technicians using identical equipment and methods;
Fig. 27 illustrates the intermediate precision of a 12 mg controlled release hydromorphone capsule by comparing dissolution curves for a capsule generated using the baseline corrected second derivative method from two different experiments conducted by two different technicians using identical equipment and methods;
Fig. 28 illustrates the intermediate precision of a 24 mg controlled release hydromorphone capsule by comparing dissolution curves for a capsule generated using the floating triangle method from two different experiments conducted by two different technicians using identical equipment and methods;
Fig. 29 illustrates the intermediate precision of a 24 mg controlled release hydromorphone capsule by comparing dissolution curves for a capsule generated using the baseline corrected second derivative method from two different experiments conducted by two different technicians using identical equipment and methods;
Fig. 24 illustrates the influence of turbidity interference in the analysis of a controlled release tramadol tablet;
Fig. 25 shows a comparison of a dissolution curve for a 12 mg controlled release hydromorphone capsule measured by a second derivative method, a baseline corrected second derivative method, and an HPLC method;
Fig. 26 illustrates the intermediate precision of a 12 mg controlled release hydromorphone capsule by comparing dissolution curves for a capsule generated using the floating triangle method from two different experiments conducted by two different technicians using identical equipment and methods;
Fig. 27 illustrates the intermediate precision of a 12 mg controlled release hydromorphone capsule by comparing dissolution curves for a capsule generated using the baseline corrected second derivative method from two different experiments conducted by two different technicians using identical equipment and methods;
Fig. 28 illustrates the intermediate precision of a 24 mg controlled release hydromorphone capsule by comparing dissolution curves for a capsule generated using the floating triangle method from two different experiments conducted by two different technicians using identical equipment and methods;
Fig. 29 illustrates the intermediate precision of a 24 mg controlled release hydromorphone capsule by comparing dissolution curves for a capsule generated using the baseline corrected second derivative method from two different experiments conducted by two different technicians using identical equipment and methods;
Fig. 30 shows a comparison of a dissolution curve for a 12 mg controlled release hydromorphone capsule measured by the floating triangle method, the baseline corrected second derivative method, and an HPLC method; and Fig. 31 shows a comparison of a dissolution curve for a 24 mg controlled release hydromorphone capsule measured by the floating triangle method, the baseline corrected second derivative method, and an HPLC method.
Figure 32 shows an illustrative fiber optic probe in accordance with a first embodiment of the present invention.
Figure 33 shows an illustrative fiber optic probe including the features of the second, third, and fourth embodiments of the present invention.
Figure 34 shows an illustrative fiber optic probe including the features of the second, third, and fourth, and fifth embodiments of the present invention.
Figure 35 shows a non-fiber optic (LED) probe in accordance with another embodiment of the present invention.
Figure 36 shows an illustrative servo function in accordance with an embodiment of the present invention.
Figure 37 is a plot of relative energy versus integration time for an illustrative probe as the servo function of Figure 36 is performed.
Detailed Description of the Preferred Embodiments One aspect of the present invention is related to an improvement in a detection system for continuously measuring the release of a drug from a pharmaceutical dosage form, the detection system comprising a dissolution vessel 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 being capable of measuring the release of the drug using fluorescence, ultraviolet (LTV), Infrared (IR), near-Infrared (hTIR), electrochemical, and Raman spectroscopy techniques.
The present invention further provides an improvement wherein the probe utilizes ultraviolet spectroscopy techniques, electrochemical techniques, Infrared (IR), near-Infrared (hTIR) or Raman spectroscopy techniques.
Another aspect of the present invention provides 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.
A method according to the present invention utilizes 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 probe capable of measuring the dissolution characteristics using LJV, IR, near-IR, fluorescence, electrochemical, and Raman spectroscopy techniques.
Yet another aspect of the present invention relates to an improvement in 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 being capable of measuring the release of the drug using fluorescence, ultraviolet, Infrared, near-Infrared, electrochemical, and Raman spectroscopy techniques. It is further provided that this aspect of the present invention may utilize at least two vessels in order to optionally hold a dissolution medium or a placebo formulation for baseline correction.
Figure 32 shows an illustrative fiber optic probe in accordance with a first embodiment of the present invention.
Figure 33 shows an illustrative fiber optic probe including the features of the second, third, and fourth embodiments of the present invention.
Figure 34 shows an illustrative fiber optic probe including the features of the second, third, and fourth, and fifth embodiments of the present invention.
Figure 35 shows a non-fiber optic (LED) probe in accordance with another embodiment of the present invention.
Figure 36 shows an illustrative servo function in accordance with an embodiment of the present invention.
Figure 37 is a plot of relative energy versus integration time for an illustrative probe as the servo function of Figure 36 is performed.
Detailed Description of the Preferred Embodiments One aspect of the present invention is related to an improvement in a detection system for continuously measuring the release of a drug from a pharmaceutical dosage form, the detection system comprising a dissolution vessel 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 being capable of measuring the release of the drug using fluorescence, ultraviolet (LTV), Infrared (IR), near-Infrared (hTIR), electrochemical, and Raman spectroscopy techniques.
The present invention further provides an improvement wherein the probe utilizes ultraviolet spectroscopy techniques, electrochemical techniques, Infrared (IR), near-Infrared (hTIR) or Raman spectroscopy techniques.
Another aspect of the present invention provides 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.
A method according to the present invention utilizes 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 probe capable of measuring the dissolution characteristics using LJV, IR, near-IR, fluorescence, electrochemical, and Raman spectroscopy techniques.
Yet another aspect of the present invention relates to an improvement in 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 being capable of measuring the release of the drug using fluorescence, ultraviolet, Infrared, near-Infrared, electrochemical, and Raman spectroscopy techniques. It is further provided that this aspect of the present invention may utilize at least two vessels in order to optionally hold a dissolution medium or a placebo formulation for baseline correction.
WO 01/16582 PCT/US00l23800 The present invention also provides an improvement in 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, electrochemical, and Raman spectroscopy techniques. It is further provided that at least two vessels in the inventive system optionally hold a dissolution medium or a placebo formulation for baseline correction.
The present invention particularly relates to detection systems for measuring dissolution characteristics of pharmaceutical dosage forms using ultraviolet, IR, near-IR, and Raman spectroscopy techniques as well as electrochemical techniques such as polarography.
The present invention also relates to 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.
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 generating 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.
Another preferred embodiment of the invention relates to a dissolution arrangement for measuring in-vitro 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 concentration of the drug to obtain a dissolution profile of the dosage form.
In a more preferred embodiment, the dissolution arrangement fiuther includes utilizing the data processor to predict future concentrations of the active agent.
In other preferred embodiments, the dissolution arrangement further includes utilizing the data processor to predict the entire dissolution profile of the active agent after at least 50 percent of the entire desired dissolution time frame has elapsed. For example, the dissolution arrangement further comprises utilizing 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 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, e.g., 48, 72 or 96 hours.
The term physical and/or chemical properties, for purposes of the present invention, means physical and/or chemical properties that are characteristic of a particular therapeutically active agent. A non-limiting list of physical and/or chemical properties includes ultraviolet absorption or radiation spectra; infrared absorption or radiation spectra;
alpha, beta or gamma radiation; electron states; polarity; magnetic resonance; concentration electro-chemical properties and the like. The physical and/or chemical properties of an agent are any property characteristics of an 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 that are detectable by a detector.
An exemplary list of agents includes chemicals, therapeutically active agents, radiation particles (e.g., D-particles); microbes such as bacteria, viruses, individual cells from a mufti-cellular organism (e.g., 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 an agent and generates data regarding about the physio-chemical property. Examples of detectors are UV-spectrophotometers, Geiger counters, fluoroscopic 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 quantify the desired physical and/or chemical data characteristic of the agent, and transmit the data to a data processor.
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 therapeutically active agent, said detector operatively associated with the dissolution medium for at least the time period required in order 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 in order 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 pmbe 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 5.0 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 software preferably continuously processes the data as it is received from the detector.
In an alternative embodiment, the apparatus fiu-ther comprises a shaft. The shaft has at least one aperture therein, which aperture 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 on a 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 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 known attachment means, 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 received in 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, e.g., therapeutically active agent, in the media surrounding the dosage form, e.g., simulated gastric 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. Moreover, the detector can be used to measure the amounts of plural agents in the surrounding media.
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 generating 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.
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 that 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 that have been tooled so as to tightly hold fiber optic probes at specified heights.
Alternatively, a dissolution apparatus utilizing a water bath may be used in place of the 1 S 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 lamp 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 circuit board that 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 spectro-meters, each of which is 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 detector, said shaft having an aperture therein that allows said detector to communicate with said external environment when said detector is received by said hollow portion. The detector may be permanently mounted to the shaft, or preferably removably mounted to the shaft to as allow a near infinite combination of shafts and detectors. To facilitate the interchangeability, the mount is preferably a universal mount that will allow an almost infinite combination of detectors and shafts.
In a preferred embodiment, the detector is capable of acquiring data characteristic of 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, with ultraviolet radiation detection being particularly preferred.
In a particularly preferred embodiment, the shaft is rotatably attached to said detector, such that the shaft is freely rotatable around the peripheral edges of the detector when the detector is situated in the hollow portion of the shaft. In this embodiment, the detector may or may not be attached in a manner to allow the detector to independently rotate about an axis within the hollow portion of the shaft, as desired.
In other preferred 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 detector. For example, the software may serve to merely store the data, or it may provide comparative analysis to reference standards, produce graphic representations of the data (e.g., 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 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 measuring 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 in the vessel just below the surface of the dissolution medium during dissolution and is lowered down into the vessel into USP sampling position immediately before analysis of the dissolution rate of the dosage form is to take place.
Most preferably, the sampling manifold is a motorized manifold that includes an internal motor drive as used in VanKel 7010 Dissolution Test Station (or equivalent). Any other device or method known in the art for raising and lowering a probe within a vessel for testing the dissolution rates of the dosage forms are also contemplated to be 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, 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, said device comprising a detector for detecting an agent in an external environment mounted to a shaft having a hollow portion capable of receiving the detector; the shaft having an aperture that allows the detector to communicate with the external environment;
and continuously retrieving data obtained from the detector 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).
Examples 1 through 5 Examples 1 through 5 illustrate various aspects of the in situ system in accordance with the present invention, methods for generating real time dissolution profiles with said in situ system, methods for predicting dissolution profiles with said in situ system, and methods for detection of low dose drugs with said in situ system. They are not to be construed to limit the claims in any manner whatsoever.
The in situ dissolution system in accordance with the present invention 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.
For examples 1 through 5, 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 S 1000 spectrometer. Data is processed using SpectraScope and Microsoft Excel 5.0 software. The detector is capable of scanning the entire LTV and visible spectrum in under 2 seconds. Comparison with the current method for dissolution analysis of 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 path length for a given drug product.
S
Fluorescence studies were conducted on a Perkin Elmer model LSS Luminescence Spectrometer. The excitation spectrum was obtained from 220 nm to 500 nm and the emission spectrum was taken from 300 to 800 nm. The dissolution bath was a Hansen Research model SRS with type II (paddle) agitation. The bath temperature was maintained at 37 +/-0.5 degrees and solution was agitated at 100 rpm.
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 (2591 Kerner Blvd., San Rafael, CA 94901) was used to mathematically model tabulated data and predict experimental results.
E$ample 1 In-situ system using an Ultraviolet-visible (UV-vis) 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) is 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 IICI
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 Slo e: 5.4292 y-intercept: 0.001935 This demonstrates the feasibility of using the fiber optical probe as a spectrometer.
Example 2 Dissolution of Tramadol 200 mg (2D 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 is 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.
Table 2 Dissolution of Tramadol aD 200 mg UV Probe vs. HPLC
4nnaal ar2a71eaea~zortase n~.w Tlmt; %OIneHW %OIuoIwd:Prob~%DImWwd:Probo . %DbwIvM:HPLC
thwnl sProbv O 1.e ~%OlaoalvM:ProbvND
0.5 0 o.e 1 2Za 1s.4 1s.2 Ie.e zl.e 1.5 ND 2a.7 I7.1 IS.I HD
I 27.e Ie.e ao.a 21.a a z.:
2.s a2.J aa.1 as.a aa.e ND
a a6.7 a7,a a9.4 a7.5 NO
a.5 a9.2 40.1 41.9 40.7 NO
4 4L0 44.0 4e.0 44.0 4 4.7 4.5 45.2 ve.l 41.7 46.7 Np 47.6 41.7 51.7 4l.a ND
' 6.6 - 61.5 5a.e 51.7 NO
4a.7 6 62.1 ea.5 ND 6Le Np 1.5 64.1 56.1 56.a 66.1 ND
7 51.! ee,7 e0.4 f7.7 NO
7.5 97.6 6e.e 12,0 6a.9 ND
a ea.e Ia.7 ea.7 sl.a e o.1 e.s et .i st.e Is.4 ezs ND
6 e Le 1a.5 e7.o e4.4 ND
a.s e4 .e ee.1 ee.2 6'e.1 No to es.7 ee.4 es.7 e7.a -~ ND
to.s Ie.a 17.e 7o~a ee.s No .
11 --Ie.s ee.e- 72.t ea.s ND
11.5 70.0 T0.5 7a.1 71.a ND
12 T0.1 7z.a 74.4 7a.t 71.0 12.5 71.. 72.1 76.7 7a.e HO
17 7a.4 74.1 70.7 74.7 ND
-Ia.G T4.6 76.1 76.0 7B.! 11D
14 75.6 T6.9 71.0 76.6 ND
14.5 7.1 77.4 10.1 71.0_ ND
16 77.6 7e. e1.1 71.1 NO
16.5 71.a 71.1 IZ2 e0.0 ND
11 7a.2 79.1 ea.1 ID.b ND
la.s 71.e e0.1 14.0 61,6 NO
1i 10.1 11.4 14.9 62.4 ND
17.6 11.a 11.t e5.9 1Z9 ND
11 11.6 eLe 16.4 ea.7 IL1 16.6 IZ.7 da.e 17.1 14.2 ND
If ea.a 1a.! 17.9 e6.0 ND
1 a.5 11.0 14.2 11.7 e6.1 ND
20 14.6 14.a 1l.4 e6.7 ND
The present invention particularly relates to detection systems for measuring dissolution characteristics of pharmaceutical dosage forms using ultraviolet, IR, near-IR, and Raman spectroscopy techniques as well as electrochemical techniques such as polarography.
The present invention also relates to 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.
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 generating 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.
Another preferred embodiment of the invention relates to a dissolution arrangement for measuring in-vitro 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 concentration of the drug to obtain a dissolution profile of the dosage form.
In a more preferred embodiment, the dissolution arrangement fiuther includes utilizing the data processor to predict future concentrations of the active agent.
In other preferred embodiments, the dissolution arrangement further includes utilizing the data processor to predict the entire dissolution profile of the active agent after at least 50 percent of the entire desired dissolution time frame has elapsed. For example, the dissolution arrangement further comprises utilizing 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 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, e.g., 48, 72 or 96 hours.
The term physical and/or chemical properties, for purposes of the present invention, means physical and/or chemical properties that are characteristic of a particular therapeutically active agent. A non-limiting list of physical and/or chemical properties includes ultraviolet absorption or radiation spectra; infrared absorption or radiation spectra;
alpha, beta or gamma radiation; electron states; polarity; magnetic resonance; concentration electro-chemical properties and the like. The physical and/or chemical properties of an agent are any property characteristics of an 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 that are detectable by a detector.
An exemplary list of agents includes chemicals, therapeutically active agents, radiation particles (e.g., D-particles); microbes such as bacteria, viruses, individual cells from a mufti-cellular organism (e.g., 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 an agent and generates data regarding about the physio-chemical property. Examples of detectors are UV-spectrophotometers, Geiger counters, fluoroscopic 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 quantify the desired physical and/or chemical data characteristic of the agent, and transmit the data to a data processor.
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 therapeutically active agent, said detector operatively associated with the dissolution medium for at least the time period required in order 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 in order 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 pmbe 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 5.0 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 software preferably continuously processes the data as it is received from the detector.
In an alternative embodiment, the apparatus fiu-ther comprises a shaft. The shaft has at least one aperture therein, which aperture 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 on a 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 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 known attachment means, 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 received in 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, e.g., therapeutically active agent, in the media surrounding the dosage form, e.g., simulated gastric 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. Moreover, the detector can be used to measure the amounts of plural agents in the surrounding media.
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 generating 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.
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 that 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 that have been tooled so as to tightly hold fiber optic probes at specified heights.
Alternatively, a dissolution apparatus utilizing a water bath may be used in place of the 1 S 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 lamp 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 circuit board that 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 spectro-meters, each of which is 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 detector, said shaft having an aperture therein that allows said detector to communicate with said external environment when said detector is received by said hollow portion. The detector may be permanently mounted to the shaft, or preferably removably mounted to the shaft to as allow a near infinite combination of shafts and detectors. To facilitate the interchangeability, the mount is preferably a universal mount that will allow an almost infinite combination of detectors and shafts.
In a preferred embodiment, the detector is capable of acquiring data characteristic of 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, with ultraviolet radiation detection being particularly preferred.
In a particularly preferred embodiment, the shaft is rotatably attached to said detector, such that the shaft is freely rotatable around the peripheral edges of the detector when the detector is situated in the hollow portion of the shaft. In this embodiment, the detector may or may not be attached in a manner to allow the detector to independently rotate about an axis within the hollow portion of the shaft, as desired.
In other preferred 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 detector. For example, the software may serve to merely store the data, or it may provide comparative analysis to reference standards, produce graphic representations of the data (e.g., 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 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 measuring 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 in the vessel just below the surface of the dissolution medium during dissolution and is lowered down into the vessel into USP sampling position immediately before analysis of the dissolution rate of the dosage form is to take place.
Most preferably, the sampling manifold is a motorized manifold that includes an internal motor drive as used in VanKel 7010 Dissolution Test Station (or equivalent). Any other device or method known in the art for raising and lowering a probe within a vessel for testing the dissolution rates of the dosage forms are also contemplated to be 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, 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, said device comprising a detector for detecting an agent in an external environment mounted to a shaft having a hollow portion capable of receiving the detector; the shaft having an aperture that allows the detector to communicate with the external environment;
and continuously retrieving data obtained from the detector 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).
Examples 1 through 5 Examples 1 through 5 illustrate various aspects of the in situ system in accordance with the present invention, methods for generating real time dissolution profiles with said in situ system, methods for predicting dissolution profiles with said in situ system, and methods for detection of low dose drugs with said in situ system. They are not to be construed to limit the claims in any manner whatsoever.
The in situ dissolution system in accordance with the present invention 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.
For examples 1 through 5, 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 S 1000 spectrometer. Data is processed using SpectraScope and Microsoft Excel 5.0 software. The detector is capable of scanning the entire LTV and visible spectrum in under 2 seconds. Comparison with the current method for dissolution analysis of 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 path length for a given drug product.
S
Fluorescence studies were conducted on a Perkin Elmer model LSS Luminescence Spectrometer. The excitation spectrum was obtained from 220 nm to 500 nm and the emission spectrum was taken from 300 to 800 nm. The dissolution bath was a Hansen Research model SRS with type II (paddle) agitation. The bath temperature was maintained at 37 +/-0.5 degrees and solution was agitated at 100 rpm.
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 (2591 Kerner Blvd., San Rafael, CA 94901) was used to mathematically model tabulated data and predict experimental results.
E$ample 1 In-situ system using an Ultraviolet-visible (UV-vis) 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) is 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 IICI
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 Slo e: 5.4292 y-intercept: 0.001935 This demonstrates the feasibility of using the fiber optical probe as a spectrometer.
Example 2 Dissolution of Tramadol 200 mg (2D 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 is 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.
Table 2 Dissolution of Tramadol aD 200 mg UV Probe vs. HPLC
4nnaal ar2a71eaea~zortase n~.w Tlmt; %OIneHW %OIuoIwd:Prob~%DImWwd:Probo . %DbwIvM:HPLC
thwnl sProbv O 1.e ~%OlaoalvM:ProbvND
0.5 0 o.e 1 2Za 1s.4 1s.2 Ie.e zl.e 1.5 ND 2a.7 I7.1 IS.I HD
I 27.e Ie.e ao.a 21.a a z.:
2.s a2.J aa.1 as.a aa.e ND
a a6.7 a7,a a9.4 a7.5 NO
a.5 a9.2 40.1 41.9 40.7 NO
4 4L0 44.0 4e.0 44.0 4 4.7 4.5 45.2 ve.l 41.7 46.7 Np 47.6 41.7 51.7 4l.a ND
' 6.6 - 61.5 5a.e 51.7 NO
4a.7 6 62.1 ea.5 ND 6Le Np 1.5 64.1 56.1 56.a 66.1 ND
7 51.! ee,7 e0.4 f7.7 NO
7.5 97.6 6e.e 12,0 6a.9 ND
a ea.e Ia.7 ea.7 sl.a e o.1 e.s et .i st.e Is.4 ezs ND
6 e Le 1a.5 e7.o e4.4 ND
a.s e4 .e ee.1 ee.2 6'e.1 No to es.7 ee.4 es.7 e7.a -~ ND
to.s Ie.a 17.e 7o~a ee.s No .
11 --Ie.s ee.e- 72.t ea.s ND
11.5 70.0 T0.5 7a.1 71.a ND
12 T0.1 7z.a 74.4 7a.t 71.0 12.5 71.. 72.1 76.7 7a.e HO
17 7a.4 74.1 70.7 74.7 ND
-Ia.G T4.6 76.1 76.0 7B.! 11D
14 75.6 T6.9 71.0 76.6 ND
14.5 7.1 77.4 10.1 71.0_ ND
16 77.6 7e. e1.1 71.1 NO
16.5 71.a 71.1 IZ2 e0.0 ND
11 7a.2 79.1 ea.1 ID.b ND
la.s 71.e e0.1 14.0 61,6 NO
1i 10.1 11.4 14.9 62.4 ND
17.6 11.a 11.t e5.9 1Z9 ND
11 11.6 eLe 16.4 ea.7 IL1 16.6 IZ.7 da.e 17.1 14.2 ND
If ea.a 1a.! 17.9 e6.0 ND
1 a.5 11.0 14.2 11.7 e6.1 ND
20 14.6 14.a 1l.4 e6.7 ND
10.6 14.e e9.4 10.1 e6.1 ND
-21 es.a ee.7 Io,a e7.e Nn 21.s 11.2 Ie.e e1.4 Ie.o ND
2x a.4 17.9 a2. o Ie.e ND
2s.s 17.4 1e.4 e2. e ea.s ND
xa 11.D Ie.t aa. a ss.e No 2a.s Ie.e ILO aa. s ao.5 No 24 Ia.4 ea.a a4. 4 st.2 n.4 I4,a 19.7 11.6 a5. 1 f 1.a NO
25 90.a 9e. 5 92.1 ND
90.5 The table clearly demonstrates that the in-situ dissolution system gives results that are precise and that correlate well to the HPLC method. Figure 4 shows the plot of the average dissolution of three tablets and the results from the HPLC method.
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 about every 2.5 seconds. The absorption at a pre-selected wavelength is plotted against time to generate a dissolution profile. Figure 5 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 such information.
Ezample 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 l, by using TableCurve 2D
program, one can fit the dissolution data into the equation as shown in Figure 6. On top of Figure 6, the best-fit equation for the data is displayed.
If one uses the 12-hour data, at 1-hour intervals and fits them to the best-fit equation, the dissolution profile generated would be as shown in Figure 7. When 16-hour data, taken at 1-hour interval, are taken to find the best-fit equation, it produced the curve of Figure 8. Note that this curve is closer to 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.
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.
Ezample 5 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 path length (20mm), a 24-hour dissolution profile is generated for hydromorphone HCl 12 mg that is comparable to that obtained from a validated HPLC method. Results are displayed in Table 3 and Figure 10.
Table 3. Data of Hydromorphone HCl 12 mg Capsule Dissolution Fiber Optics v. HPLC
Hydromorphone d HCI
Dissolve HourFiberHPLCHourFiberHPLCHourFiberHPLCHourFiberHPLC
0 1.7 0 0.172.76 6.1738.9 12.262 18.1779 0.335 6.3339.2 12.362.5 18.3379.7 0.57.18 6.540 12.563.2 18.579.8 0.678.67 6.6740.6 12.763.7 18.6780.2 0.8310 6.8341.5 12.864.4 18.8380.5 t 11.411.37 42.2 13 64.9 19 80.8 1.1712.5 7.1743 13.265.5 19.1781.2 1.3313.7 7.3343.5 13.366 19.3381.6 1.514.8 7.544.2 13.566.4 19.582 1.6716 7.6744.9 13.767 19.6782.1 1.8317.2 7.8345.7 13.867.5 19.8382.6 2 18.118.28 46.356 14 68 20 82.9 2.1719.3 8.1746.8 14.268.5 20.1782.9 2.3320.1 8.3347.2 14.369 20.3383.5 2.521.2 8.548.4 14.569.6 20.583.6 2.6721.8 8.6749.2 14.770.2 20.6784 2.8322.8 8.8349.6 14.870.7 20.8384.1 3 23.8 9 50.3 15 71.3 21 84.4 3.1724.7 9.1751.1 15.271.5 21.1784.6 3.3325.4 9.3351.8 15.372.1 21.3384.9 3.526.1 9.552.3 15.572.3 21.585.2 3.6726.9 9.6753.3 15.772.9 21.6785.4 3.8328 9.8353.7 15.873.4 21.8385.5 4 28.731.810 54.4 16 73.9 22 85.7 4.1729.7 10.255.1 16.274.3 22.1786.2 4.3330.5 10.355.9 16.374.8 22.3386.3 4.531.4 10.556.2 16.575.3 22.586.6 4.6732.2 10.757.1 16.775.6 22.6787.1 4.8332.8 10.857.3 16.875.8 22.8387.1 5 33.7 11 58 17 76.5 23 87.1 5.1734.4 t 58.6 17.276.9 23.1787.3 1.2 5.3335.3 11.359.1 17.377.4 23.3387.5 5.536 11.559.7 17.577.9 23.587.7 5.6736.7 11.760.2 17.777.9 23.6787.9 5.8337.5 11.860.9 17.878.4 23.8387.9 6 38.3 12 61.473.818 78.990.324 88.399.8 Svstem Design Figure 11 shows an illustrative system 1 in accordance with an embodiment of the present invenrion. The system 1 includes a computer 20, a display screen 10, a keyboard 40, and a mouse 30. A plurality (in this case seven) of CCD's (charge coupled devices) are coupled to the computer 20. In this regard, the CCD's can be stand-alone external CCD
spectrometers (connected to the computer 20 via, for example, a PCMIA card), or can be internal CCD
spectrometers comprised of a closed optics bench mounted in card slots of a PCB (printed circuit board) in the computer 20. Examples of the internal CCD spectrometers include the PC Plug-In Fiber Optic Miniature Spectrometer manufactured by Ocean Optics, and the Spectrophotometer manufactured by Hewlett Packard.
As shown in Figure 11, each of seven vessels 60 has a fiber optic UV probe 70 and dissolution paddle (not shown) disposed therein. Typically, one of the vessels 60 will contain the dissolution medium alone, or a placebo formulation in the dissolution medium, in order to provide a baseline spectra (e.g., to be used for a baseline correction calculation). The remaining six vessels 60 can hold the samples to be tested. Naturally, the system can also be configured with more or fewer than seven vessels. A light source 100, for example an LS-1 Deuterium light source as described above, is coupled to each of the fiber optic UV probes 70.
Each W probe 70 extends from the light source 100, into the vessel 60, and is coupled at its other end to a respective CCD spectrometer S0. Preferably, the internal core of the fiber consists of fused silica, which allows UV radiation to be efficiently propagated.
Figure 32 shows a first embodiment of the fiber optic W probe 70 having a shaft 101, at the remote end of which (not shown) is connected a light source 100 and a CCD
spectrometer 50.
Shaft 101 contains a pair of fibers (each preferably comprised of fused silica). At the proximal end of shaft 101, probe 70 has a detecting end 103 that contains a lens for focusing light that travels through the fibers. Detecting end 103, while being cylindrically-shaped in this embodiment, can have any suitable shape, so long as it does not interfere with the dissolution being detected. As shown in Figure 32, a flow cell 105 is formed as a bore, opening, aperture, or WO 01/16582 CA 02383906 2002-02-27 pCT/US00/23800 window through end 103. Dissolution medium flows freely through the flow cell 105, such that the dissolution within the medium can be measured.
UV radiation is transmitted from the source lamp through a first one of the fibers (which extends through shaft 101 into the probe) and through a quartz lens seated directly above the flow cell 105. UV radiation travels through flow cells 105 and is reflected off a mirror positioned at the terminal end of the probe on surface 109. The radiation is then directed back through the flow cell 105 and quartz lens into a second one of the fibers where it travels through shaft 101 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. As explained above, radiation returns from the fiber optic probe to the CCD
spectrometer where it is analyzed and quantitated. 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, preferably 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 system of Figure 11 may utilize open (i.e., uncovered) vessels or, most preferably, may utilize a "closed" (i.e., covered) vessel design as shown in Figure 12. An example of a suitable closed vessel is a Distek 5100 bathless unit. The major advantage of this closed design is to minimize loss of dissolution media.
In one embodiment of the system of Figure 11, probes 70 are inserted into vessels 60 for measurement of dissolution, and are held approximately midway between the surface of the dissolution medium and the bottom of the vessels 60. However, in certain applications (such as immediate release tablets), the presence of probes 70 within the medium may interfere with proper dissolution of the dosage into the medium, and readings taken by probes 70 that have been situated within vessels 60 may not accurately reflect the true dissolution rates. However, the USP currently requires that the dissolution medium be sampled approximately midway WO 01/16582 CA 02383906 2002-02-27 pCT/US00lZ3800 between the surface of the dissolution medium and the bottom of the vessels.
Accordingly, system 1, as shown in Figure 11, may alternatively use a dipping manifold to move the dip probes between a first position just below the surface of the dissolution medium and a second position midway between the surface of the dissolution medium and the bottom of the vessel. In this embodiment, the dipping manifold can be controlled to automatically dip the probes 70 into the second position only immediately or a short time period before readings are to be taken (e.g., every 1, 2, 5, or 10 minutes), and then to raise the probes into the first position when readings are not being taken. Alternatively, the dipping manifold can be controlled so as to selectively dip probes 70 into the vessels 60 between the first and second positions (or at any other position relative to the vessel). In this manner, should the operator of system 1 suspect that there is a turbidity problem, probes 70 can selectively be dipped into the medium (or raised within the medium) to a point outside the zone of disturbance caused by the agitation of the paddles within the medium. An example of a suitable dipping manifold is the manifold in the VanKel 7010 Dissolution Test Station. However, any other motorized mechanism suitable for moving the dip 1 S probes between the first and second positions can alternatively be used.
In the first embodiment of probe 70, as shown in Figure 32, the tip 111 of detecting end 103 of probe 70 is flat and the shaft 101 and detecting end 103 have the same diameter. A
potential problem associated with in situ probes is that bubbles may be formed when the probe is inserted into vessel 60. If these bubbles enter the flow cell, they may cause faulty spectral readings, and the resulting measurements may not be accurate. Therefore, in a second embodiment of probe 70, illustrated in Figure 33, the tip 112 of detecting end 103 of probe 70 is comically shaped. The pointed (or conical) tip 112 of probe 70 is intended to reduce the occurrence of bubbles within the fluid when probe 70 is first inserted into the fluid in vessel 60 for measuring the dissolution. In a third embodiment of probe 70, also illustrated in Figure 33, shaft 101 has a smaller diameter than detecting end 103 in order to reduce the profile of the probe 70 and reduce the hydrodynamic interference generated by the probe in the dissolution media.
In a fourth embodiment of probe 70, illustrated in Figure 34, detecting end 203 of probe 70 has a flow cell 205, bounded by upper surface 207 and lower surface 209, and the opposing ends of detecting end 203 are joined by a single arm 204, which is situated on the side of detecting end 203. This single arm construction is intended to enhance the flow through flow cell 205 and prevent particles from being caught within flow cell 205.
It should be noted that although in Figures 33 and 34, the tip 112 of detecting end 203 of probe 70 is comically shaped or pointed (as in the second embodiment described above) and the shaft 101 has a reduced profile (as in the third embodiment), the probe in accordance with the third embodiment may alternatively have a flat detecting end 103 and a uniform profile (as in the first embodiment). 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.
Figure 12 shows a vessel 60 with a dissolution paddle 90 disposed therein. The design of such a probe has the advantage of not causing flow aberration, since an additional probe need not be submerged in the dissolution media. Figure 13 shows the dissolution paddle 90 of this embodiment in greater detail. Fiber optic UV probe 70 is shown disposed within the hollow shaft of the dissolution paddle 90. In addition, a temperature sensor may optionally be disposed within the shaft of the paddle. Alternatively, the temperature sensor can be disposed elsewhere within the vessel 60, or eliminated altogether (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 Figure 12, a window 110 is provided on the shaft in order to allow the dissolution medium to flow through the shaft, thereby providing optical connectivity between the probe and the dissolution medium. A stirring motor 120 is also provided for rotation of the dissolution paddle 90. The stirring motor may be controlled via the computer or in any other known manner.
In a simple embodiment, the motor simply can be controlled by a switch.
As described above, the dissolution vessel temperature in the in-situ system can be controlled by a water bath in which vessels are submerged in order to maintain appropriate temperature. Alternatively, as shown in Figure 12, the dissolution vessel temperature in the in-situ system can be controlled by a bathless configuration, in which each vessel is surrounded by a heating element. This configuration reduces the size of the equipment and consequently the bench space and minimizes maintenance. It also allows temperature control of each vessel WO 01/16582 PCT/US00l23800 individually and also helps to minimize vibration associated with thermocirculation. A heating element appropriate for the bathless configuration is commercially available from Distek, Inc.
In an alternate design to the above-described general embodiments, probes 70 can be situated outside the dissolution vessels 60. In such an embodiment, near IR
that has limited interference from the container, such as glass vessel, is good candidate for use with such a detection probe. This embodiment avoids the issues of turbulence of the medium potentially interfering with measurements or the presence of the probes 70 within the medium potentially interfering with the dissolution of the medium.
The present invention can be practiced by detection systems other than those described above. For example, other fiber optic systems can be used, such as (1) Fluorescence, as described in the publication by Glazier, S.A. et al., Analytical Letters (1995) 28, 2607-24, (2) Infrared techniques, as described by Krska, R. et al. in Appl. Phys. Lett.
(1993) 63, 1868-70, (3) Near IR and Raman techniques, as described by Cram, D.J. and Hammond, G.S., Organic Chemistry, McCrraw-Hill (1959), all of which are hereby incorporated by reference, either with a grating or interferometer system. Each of these is a potentially powerful technique useful for dissolution testing. The techniques can be used with fiber optic spectrometers similar to that of UV, and these technologies are incorporated into the in-situ system similar to that for UV
detection.
In addition, an electrochemical detection system, such as quantitative electrochemical techniques as described by Cooper, J.C. and Hall, E.A., 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 can be used in the in-situ system with different electrode designs, such as platinum or glassy carbon electrodes, for evaluation of different products.
Furthermore, 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 WO 01/16582 PCT/USOOlZ3800 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 can be used the in-situ system as described herein.
Moreover, a non-fiber optic light source within probe 70 may be used as well.
In such an embodiment, as shown in Figure 35, the light is generated by an array of light emitting diodes (LEDs) 310 situated at the top 307 of flow cell 305. A number of LEDs (e.g, between 2 and 10), each with a different peak wavelength, are preferably placed at the top 307 of flow cell 305. A
conventional (e.g., silicon) photodiode would be situated at the bottom 309 of flow cell 305 in order to detect the amount of light that passes through the flow cell. A
"scan" is then acquired by illuminating the medium within the flow cell 305 with each diode in sequence.
The only connection from probe 70 is an electrical cable 313, which contains power, data and control wires. In addition, different types of detectors may also be used, such as lead sulfide, gallium arsenic (GaAs), gallium (Ga) and indium antimony (InSb).
Use of LEDs as a light source may be applied for dissolution testing, reaction monitoring, general laboratory solution analysis, turbidity measurements and pipeline analysis. Currently, LEDs are available in the NIR, UV, and visible regions. In general, the use of LEDs as a light source is appropriate in applications in which the spectroscopic investigation is required only for a limited number of wavelengths, such as quality control dissolution testing for a pharmaceutical dosage form. In this regard, the number of wavelengths which can be used in an LED light source is limited to the number of LEDs which can be housed in the detectors.
Another feature of the present invention is a servo system for achieving a constant energy level on all spectrometers used in dissolution testing. Generally, the servo function acquires WO 01/16582 CA 02383906 2002-02-27 pCT/US00/23800 reference spectra at varying integration times in order to achieve a given energy level. Longer integration times will produce a larger signal.
As shown in Figure 36, the servo is controlled by a control module, which acquires reference spectra at varying integration times in order to achieve a given energy level. First, the servo acquires a reference scan at a lowest predetermined integration time.
The servo then acquires a second reference scan with a new integration time. This procedure is repeated iteratively until an integration time is chosen that produces the desired level of energy, called the Target Percent Relative Energy.
In order to perform these extrapolations accurately, the servo assumes that the spectrometer's intensity response is relatively linear over short integration time intervals and that the intensity response is monotonically increasing over the range from the lowest predetermined integration time (e.g., 3.6 ms) to a largest predetermined integration time (e.g. 6,534.7 ms). As set forth below, if these assumptions are not valid for a particular spectrometer, then that spectrometer is considered to be non-functional and an error message is generated.
In the following discussion, the servo function will be explained in connection with a system in which the lowest predetermined integration time is 3.6 ms (which is the minimum integration time of a Zeiss spectrometer) and 6,534.76 ms (which is the maximum integration time of the Zeiss spectrometer).
Two parameters are associated with the servo function, namely the Target Percent Relative Energy and the Target Precision. The default values for these parameters are 80% and 0.1%, respectively. However, other values may alternatively be used. The servo starts with an Integration Time of 3.6 ms (the lowest predetermined integration time), by acquiring a data point using this value and obtaining the relative energy from the spectrometer. The Servo will then perform a linear extrapolation using the measured relative energy from the last data step in order to determine what the new integration time should be in order to obtain the target relative energy.
The servo computes the new integration time for each subsequent data step using the formula ITN = IT * (TRE/MRE), where:
WO ~l/16$82 CA 02383906 2002-02-27 pCl,/[JS~~n380~
ITN is the New Integration Time;
IT is the Integration Time;
THE is the Target Relative Energy (percent); and MRE is the Measured Relative Energy (percent).
The servo function terminates whenever MRE is within Target Precision units from the Target Percent Relative Energy. The servo calculates a Low Limit (Target Percent Relative Energy - Target Precision) and a High Limit (Target Percent Relative Energy +
Target Precision). The servo then terminates at the point that the Measured Relative Energy is greater than or equal to the Low Limit and Measured Relative Energy is less than or equal to the High Limit.
For example, using the starting values of a Target Relative Energy of 80% and a Target Precision of 0.1%, if an integration time of 3.6 ms resulted in a measured relative energy of 2%, then the integration time would need to be increased by approximately 40 times (i.e., the ratio of Target Relative Energy to Measured Relative Energy, or 80% / 2%). Accordingly, the calculated new integration time is 144 ms (i.e., 40 times 3.6 ms). Assuming that the spectrometer is perfectly linear, this result provides a measured relative energy of 80% for an integration time of 144 ms, meaning that the servo could terminate its loop after just two steps.
However, this is seldom the case, as illustrated by the following table. In step 2, the integration time of 144 ms derived above results in a measured relative energy of 90%. The ratio of THE to MRE of 0.89 indicates that the integration time needs to be decreased from 144 ms to 128 ms. Then, as shown in step 3, the integration time of 128 ms results in a reduced measured relative energy of only 85%, and the resulting ratio of THE to MRE of 0.94 provides a slightly smaller new integration time of 120.5 ms.
In step 4, the integration time of 120.5 results in a further relative energy of 81%, which is still slightly outside the desired limits of 80% ~ 0.1 %. The resulting ratio of THE to MRE of 0.99 provides a new integration time of 119Ø In this example, an integration time of 119.0 ms results in precisely 80% relative energy, and the iterative process is terminated at step 5.
Table 4 Step IT MRE TRE/MRE ITN
Ratio 1 3.6 2 40.00 144.0 2 144.0 90 0.89 128.0 3 128.0 85 0.94 120.5 4 120.5 81 0.99 119.0 119.0 80 1.00 119.0 5 The data from the above reference scans for obtaining the Target Relative Energy set forth below in Table 4 are plotted in Figure 37. The plotted line in Figure 37 illustrates that the spectrometer used is slightly non-linear, but within acceptable limits.
As set forth above, the system preferably generates error messages when a spectrometer fails to perform within acceptable limits for the servo system. One indicator of a non-functioning spectrometer is a non-linear intensity response, which occurs when MRE/MREp _<
0.1 * ITN/IT.
The servo system assumes that the spectrometer intensity response is relatively linear such that the increases and/or decreases in relative energy are relatively proportional to the increase and/or decrease in the integration time, from one step to the next. A non-linear intensity response occurs when the proportional relative energy increase/decrease is less than one/tenth that of the integration time increase/decrease. If the intensity Response is non-linear, the spectrometer is considered to be non-functional and an error message is generated. Another instance of a non-functioning spectrometer is caused by the use of an extremely high light intensity, which occurs whenever MRE = 100 and IT = MinIntegrationTime, i.e., the relative energy is equal to 100%
and the integration time is equal to the minimum integration time. In addition, a non-functioning spectrometer can also be caused by a high light intensity, which occurs whenever MRE >
HighLimit and IT = MinIntegrationTime, i.e., the relative energy is greater than the desired HighLimit and the integration time is equal to the minimum integration time.
Similarly, a non-functioning spectrometer may be caused by the use of low light intensity, which occurs whenever MRE < LowLimit and IT > MaxIntegrationTime, i.e., the relative energy is less than the desired LowLimit and the integration time is equal to the maximum integration time. If any of these conditions is detected, a respective error message is generated. In response, the user will investigate the light intensity, and, if appropriate, lower (or increase) the light intensity to an acceptable level. In addition, if the servo function performs more than a predetermined maximum number of iterations (e.g. 100) without reaching the Target Relative Engery (+/-Target Precision), an error message will be generated.
Spectral Analysis Method With Scattering Compensation As set forth above, in accordance with an embodiment of the present invention, the data received from each probe is analyzed to determine the percentage of active agent dissolved over time. While this embodiment of the invention will be discussed with reference to the system of Figure 11, other in situ dissolution systems described herein may alternatively be employed.
One of the major obstacles in the development of analytical systems with in-situ dissolution monitoring techniques is that the in situ nature of the method excludes any sample pretreatment. A standard practice in spectroscopic analysis is to filter the sample solution prior to any optical analysis. The reason for this is simple: any particulate suspended in the sample can cause scattering that may interfere with the spectroscopic analysis of the compound under study. However, since an in situ dissolution technique inherently forbids this sort of sample pretreatment, an alternative approach is needed.
The simplest approach would to utilize a single point baseline correction where the absorbance of a single point is subtracted from the absorbance of the analytical measurement.
This works well if the scattering level is small in comparison to the level of the analytical absorption (as in the case of tramadol). However, in situations where the scattering response is the dominant spectra, a different approach is needed.
Tangential Peak Area Spectral Analysis Method In view of the scattering problems set forth above, a mathematical method is needed that selectively analyzes only the region of the spectrum that results from the absorption of the analyte. One method that accomplishes this goal is the "floating triangle"
method, which was used to quantitate the amount of hydromorphone HCl in thel2 mg capsules of Example 5 set forth above The mathematical basis of this quantitation method is illustrated in Figure 14.
Since the height h of the triangle is independent of the slope and level of the baseline b, this measurement can be directly related to the amount of hydromorphone HCl in solution.
Although this method does provide adequate selectivity towards hydromorphone, an improved quantitation method that is less susceptible to scattering interference is desirable.
In accordance with a tangential peak area method in accordance with the present invention, the area of a right triangle is subtracted from the total area under the curve of a relevant spectral region. The area of the right triangle, which is described in more detail below, closely approximates the remaining scattering contribution. Figure 15 shows how the area under the curve is first defined by the spectral range of analyte (260-296 nm for hydromorphone HCl).
A baseline subtraction of the curve is then applied. The area of the baseline-subtracted region is then determined by a trapezoidal approximation (from the Trapezoidal Rule, see Stewart, James, Calculus, 2°d edition 1991, pp.455).
The measured peak area (MPA), which is free from scattering interference, is then determined by subtracting the area of the right triangle from the total area under the curve, wherein the right triangle is defined by the following points baseline (i), f(i), and baseline (ii), and the base of the triangle is defined by the baseline(i to ii), as shown in Figure 16. In Figure 16, f(x) intersects the baseline at the higher end (point ii) of the spectral region. As one of ordinary skill in the art will appreciate, however, this is merely illustrative, and it is possible that other spectrums may have a baseline value which intersect f(x) at the lower end (i) of the spectral region. The MPA is proportional to the amount of drug substance in solution.
The MPA can be calculated in the following manner. As the calculations are relatively simple, they are particularly well suited for real-time data generation:
The baseline measurement is first subtracted from every point in the spectral region (baseline corrected).
2. The Area Under the Curve (AUC) is then calculated using the Trapezoidal Rule, which divides up the area under the curve into trapezoids and then calculates the area of the trapezoids. The AUC is then defined as the sum of areas of the individual trapezoids. The area of each trapezoid is defined by the equation A, = 0x (y'-' 2 y' ~ , where A; is the area of the i'~
interval (trapezoid), and y;_1 and y; are the absorbance values for the given and the previous interval. Therefore, the area under the curve (AUC) is given by the equation (y1-1 + y!
A.U.C.='~ ~X
Figure 15 shows this area under the curve as the striped region. This area is not corrected for scattering and is not used directly for analytical measurements in this embodiment. In order to correct for scattering, the portion of the area that contains the scattering interference must be removed. This is accomplished by subtracting everything but the analytical "hump" that results from the absorption of our analyte. This can be very closely approximated by removing the area of the right triangle, as shown in Figure 16. The area of the right triangle (ART) is defined by the equation ART = ~ 2~y , which is one half the base times the height, where the base 1 S 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 are determined, the measured peak area (MPA) is defined as the difference of the two:
Measured Peak Area = AUC - ART. This measurement can then be used to generate analytical data.
Example 6 In order to demonstrate how the tangential peak area method more accurately calculates the amount of analyte dissolved, dissolution tests were conducted on 12 mg., 16 mg, 24 mg, and 32 mg hydromorphone capsules. The capsules have the following ingredients:
Dosage and Weight Ingredients Weight Ratio (%) CAPSULES EUDRAGIT RSPO 63.75 Total Wt. Stearyl alcohol 22.50 120 mg. Ethocel Standard 7 3.75 Premium CAPSULES EUDRAGIT RSPO 63.75 Total Wt. Stearyl alcohol 22.50 160 mg. Ethocel Standard 7 3.75 Premium CAPSULES EUDRAGIT RSPO 63.75 Total Wt. Stearyl alcohol 22.50 240 mg. Ethocel Standard 7 3.75 Premium CAPSULES EUDRAGIT RSPO 63.75 Total Wt. Stearyl alcohol 22.50 320 mg. Ethocel Standard 7 3.75 Premium Dissolution data was obtained using the HPLC method at 1 hour, 2 hours, 12 hours, 18 hours, and 24 hours, in situ using the floating triangle method (shown in Figure 14) sampling every 10 minutes, and in situ using the tangential peak area method (shown in Figure 15) sampling every 10 minutes.
The HPLC data was generated as follows. Dissolution was carried out using USP
Apparatus 1 Basket Method <711> at 100 RPM. The dissolution media was 900 ml of simulated intestinal fluid without enzymes plus 3 grams sodium chloride per liter at 37° C. The samples used were 12 mg, 24 mg and 32 mg capsules of controlled release hydromorphone as described above. The samples were withdrawn at 1 hour, 2 hours, 12 hours, 18 hours and 24 hours and analyzed by HPLC (High Pressure Liquid Chromatography) for hydromorphone HCI.
The samples were then separated on a reverse phase C,8 Waters Nova-Pak column at 30° C, using a mobile phase at pH of 2.9 consisting of sodium dodecyl sulfate, acetonitrile, sodium phosphate monobasic, and water. UV absorbance detection at 280 nm was used for quantitative determination.
The data for the in situ dissolution was generated using the dissolution apparatus of Figure 11, using USP Apparatus 2 Paddle Method at 100 RPM. The dissolution media was 500 ml of simulated intestinal fluid (without enzyme) maintained at 37° C
with 3 grams of sodium chloride per liter. The samples used were 12 mg, 24 mg and 32 mg capsules of controlled release hydromorphone as described above. The dissolution rated was continuously monitored by a UV
Fiber Optic absorbance dip probe, with a 20 mm path length and manufactured by Ocean Optics.
The dip probe was placed in the dissolution vessel, adjacent to the mixing shaft as shown in Figure 11. The deuterium light source was manufactured by Oriel Instruments, and the spectrometer was an Ocean Optics PC1000 Fiber Optic CCD Spectrometer. An absorbance spectrum of the dissolution media was generated every 10 minutes for a period of 24 hours.
The measured spectrums were then processed in accordance with the floating triangle method of Figure 14, and the tangential peak area method of Figures 15 and 16.
The results of these tests are shown in Figures 17 through 20, which demonstrate that the tangential peak area method in accordance with the invention provides results that are equal to or superior to those generated with the floating triangle method.
The most dramatic increase in accuracy is seen for the l2mg sample (Figure 17), where the improved floating triangle method corresponds quite nicely with the HPLC
data. This is probably due to the use of a greater number of wavelengths in the Tangential Peak Area Method (TPAM)(19 points: 260, 262, ... 296 nm) as compared to the floating triangle method (3 points:
260, 280, 310), which increase sensitivity and selectivity. This benefit is most evident at the 12 mg capsule because the 12 mg capsule has the smallest amount of hydromorphone and, therefore, is more susceptible to inaccuracies flowing from scattering affects.
The underlying data for the graphs of Figures 17 through 19 are set forth below in Tables 5 through 8:
Table 5: HHCR 12 mg Time Floatin Trian 1e TPAM 12m HPLC
Method 0.0 0.00% 0.01%
hr 0.2 0.28% 5.36%
hr 0.3 8.76% 9.04%
hr 0.5 9.91% 10.91%
hr 0.7 11.11 % 11.68%
hr 0.8 12.43% 13.21 hr 1.0 13.99% 14.48% 8.80%
hr 1.2 15.20% 15.79%
hr Time Floatin Trian 1e TPAM 12m HPLC
Method 1.3 16.49% 17.23%
hr 1.5 17.87% 18.35%
hr 1.7 18.91% 19.96%
hr 1.8 2 21.11%
hr 0.31%
2.0 ____ 22.58% 16.43%
hr _ 21.32%
2.2 23.00% 3.32%
hr 2 2.3 23.93% _ hr _ 25.00%
2.5 - -25.16% - 26-.09%
hr 2.7 26.02% 27.63%
hr 2.8 26.89% 28.47%
hr 3.0 28.11 % 29.31 hr 3.2 29.07% 30.36%
hr 3.3 30.36% 31.07%
hr 3.5 31.20% 32.83%
hr 3.7 32.26% 33.35%
hr 3.8 33.29% 34.63%
hr 4.0 34.43% 35.79%
hr 4.2 35.37% 36.68%
hr 4.3 36.52% 37.62%
hr 4.5 37.11 % . 39.04%
hr 4.7 38.45% 40.01 hr 4.8 40.00% 40.78%
hr 5.0 41.18% 42.34%
hr 5.2 42.04% 43.42%
hr 5.3 42.75% 44.70%
hr 5.5 43.43% 45.38%
hr 5.7 44.28% 46.17%
hr 5.8 45.31 % 46.96%
hr 6.0 46.18% 48.00%
hr 6.2 46.98% 49.28%
hr 6.3 48.22% 49.99%
hr 6.5 49.14% 50.92%
hr 6.7 50.21 % 51.52%
hr 6.8 50.91 % . 52.81 hr 7.0 51.90% 53.54%
hr 7.2 52.77% 54.44%
hr 7.3 53.65% 55.47%
hr 7.5 54.84% 56.49%
hr 7.7 55.63% 57.85%
hr 7.8 56.80% 58.14%
hr 8.0 57.66% 59.32%
hr 8.2 58.72% 60.18%
hr 8.3 59.77% 61.41 hr 8.5 60.20% 62.73%
hr 8.7 60.73% 63.12%
hr 8.8 61.57% 63.66%
hr 9.0 62.06% 64.61 hr 9.2 63.22% 65.04%
hr Time Floatin Trian 1e TPAM 12m HPLC
Method 9.3 63.78% 66.53%
hr 9.5 64.70% 67.34%
hr.
9.7 65.56% 68.01 hr 9.8 66.42% 68.85%
hr 10.0 66.70% 69.59%
hr 10.2 67.10% 69.78%
hr 10.3 67.46% 70.05%
hr 10.5 68.05% 70.87%
hr 10.7 68.73% 71.75%
hr 10.8 69.46% 72.29%
hr 11.0 70.47% 72.77%
hr 11.2 71.47% 74.08%
hr 11.3 72.25% 74.46%
hr 11.5 73.04% 75.15%
hr 11.7 73.66% 76.47%
hr 11.8 74.74% 77.01 hr 12.0 75.10% 77.85% 77.77%
hr 12.2 74.86% 78.62%
hr 12.3 75.16% 78.25%
hr 12.5 75.28% 78.30%
hr 12.7 75.83% 78.84%
hr 12.8 76.16% 79.42%
hr 13.0 77.09% 79.66%
hr 13.2 77.73% 80.74%
hr 13.3 78.77% 81.32%
hr 13.5 79.80% 82.12%
hr 13.7 79.98% 83.24%
hr 13.8 81.03% 83.63%
hr 14.0 81.44% 84.39%
hr 14.2 81.49% 85.19%
hr 14.3 82.12% 85.16%
hr 14.5 82.37% 85.87%
hr 14.7 82.95% 86.31 hr 14.8 83.53% 86.72%
hr 15.0 83.92% 87.25%
hr 15.2 84.15% 87.61 hr 15.3 84.71 % 87.92%
hr 15.5 85.11 % 88.62%
hr 15.7 85.29% 88.68%
hr 15.8 86.04% 88.97%
hr 16.0 85.93% 89.55%
hr 16.2 86.26% 89.68%
hr 16.3 87.13% 90.12%
hr 16.5 87.02% 90.96%
hr 16.7 87.42% 90.71 hr 16.8 87.78% 91.26%
hr 17.0 88.15% 91.40%
hr 17.2 88.29% 91.84%
hr Time Floatin Trian TPAM 12m HPLC
1e Method 17.3 88.93% 91.94%
hr 17.5 89.02% 92.53%
hr 17.7 89.26% 92.76%
hr 17.8 89.79% 92.96%
hr 18.0 89.73% 93.60%
hr 18.2 90.09% 93.51 hr 18.3 90.36% 93.95%
hr 18.5 90.61 % 94.39% 95.15%
hr 18.7 90.47% 94.37%
hr 18.8 90.91 % 94.45%
hr 19.0 90.89% 94.56%
hr 19.2 91.00% 94.55%
hr 19.3 91.13% 95.18%
hr 19.5 91.46% 95.32%
hr 19.7 91.43% 95.95%
hr 19.8 91.62% 95.42%
hr 20.0 92.06% 95.93%
hr 20.2 92.38% 96.12%
hr 20.3 92.63% 96.48%
hr 20.5 92.95% 96.55%
hr 20.7 93.22% 97.16%
hr 20.8 93.00% 97.14%
hr 21.0 93.23% 97.29%
hr 21.2 93.09% 97.75%
hr 21.3 93.41 % 97.43%
hr 21.5 93.51 % 97.31 hr 21.7 93.81 % 98.09%
hr 21.8 93.98% 98.26%
hr 22.0 94.25% 98.50%
hr 22.2 94.43% 98.47%
hr 22.3 94.27% 98.45%
hr 22.5 94.37% 98.40%
hr 22.7 94.82% 99.18%
hr 22.8 95.08% 99.16%
hr 23.0 94.80% 98.85%
hr 23.2 95.36% 98.95%
hr 23.3 95.09% 99.51 hr 23.5 95.55% 99.55%
hr 23.7 95.72% 99.64%
hr 23.8 96.06% 99.97%
hr 24.0 100.05% 100.07%
hr Table 6: HHCR 24 mg Time Floatin Trian 1e TPAM 24m HPLC
24 m 0.0 0.27% 0.10%
hr 0.2 6.31 % 7.58%
hr Time- Floatin Trian 1e TPAM 24m HPLC
24 m 0.3 8.38% 9.98%
hr 0.5 10.11 % 11.83%
hr 0.7 11.82% 13.56%
hr 0.8 13.13% 14.85%
hr 1.0 14.54% 16.22% 13.14%
hr 1.2 15.85% 17.41 hr 1.3 17.37% 18.93%
hr 1.5 18.59% 20.30%
hr 1.7 19.88% 21.59%
hr 1.8 21.16% 22.84%
hr 2.0 22.45% 24.04% 19.85%
hr 2.2 23.78% 25.66%
hr 2.3 24.94% 26.85%
hr 2.5 26.39% 28.23%
hr 2.7 27.57% 29.37%
hr 2.8 28.79% 30.70%
hr 3.0 29.99% 32.16%
hr 3.2 31.33% 33.43%
hr 3.3 32.58% 34.60%
hr 3.5 33.89% 36.06%
hr 3.7 35.11 % 37.22%
hr 3.8 36.59% 38.68%
hr 4.0 37.51 % 39.78%
hr 4.2 39.01 % 41.28%
hr 4.3 40.20% 42.29%
hr 4.5 41.43% 43.64%
hr 4.7 42.62% 45.10%
hr 4.8 44.07% 46.21 hr 5.0 45.28% 47.49%
hr 5.2 46.62% 48.85%
hr 5.3 47.70% 49.94%
hr 5.5 49.18% 51.49%
hr 5.7 50.27% 52.62%
hr 5.8 51.34% 53.49%
hr 6.0 52.50% 54.72%
hr 6.2 53.73% 56.04%
hr 6.3 54.92% 57.24%
hr 6.5 56.01 % 58.32%
hr 6.7 57.10% 59.48%
hr 6.8 58.24% 60.61 hr 7.0 59.27% 61.74%
hr 7.2 60.41 % 62.88%
hr 7.3 61.53% 64.02%
hr 7.5 62.63% 65.10%
hr 7.7 63.56% 66.04%
hr 7.8 64.54% 67.21 hr 8.0 65.51 % 68.08%
hr 8.2 66.76% 69.11 hr WO 01/16582 PCT/US00l23800 Time Floatin Trian 1e TPAM 24m HPLC
- 24 m 8.3 67.65% 70.31 hr 8.5 68.73% 71.31 hr 8.7 69.71 % 72.48%
hr 8.8 70.54% 73.08%
hr 9.0 71.42% 73.89%
hr 9.2 72.36% 75.01 hr 9.3 73.51 % 76.03%
hr 9.5 74.25% 76.78%
hr 9.7 75.02% 77.84%
hr 9.8 75.74% 78.35%
hr 10.0 76.67% 79.28%
hr 10.2 77.33% 80.13%
hr 10.3 78.17% 80.93%
hr 10.5 78.74% 81.54%
hr 10.7 79.49% 82.37%
hr 10.8 80.32% 83.29%
hr 11.0 80.74% 83.49%
hr 11.2 81.75% 84.55%
hr 11.3 82.25% 85.07%
hr 11.5 83.16% 85.92%
hr 11.7 83.62% 86.38%
hr 11.8 84.28% 87.04%
hr 12.0 84.87% 87.74% 84.15%
hr _ _ 88.21 % -12.2 85.35%
hr _ 12.3 - - 85.98% 88.82% -hr 12.5 86.44% 89.29%
hr 12.7 86.92% 89.75%
hr 12.8 87.28% 90.13%
hr 13.0 87.94% 91.00%
hr 13.2 88.29% 91.21 hr 13.3 88.84% 91.62%
hr 13.5hr 89.40% 92.14%
13.7 - - $9.81 % 92.60%
hr-13.8 - - 9.42% 93.01 hr 14.0 90.97% 93.60%
hr 14.2 91.34% 94.02%
hr 14.3 91.47% 94.23%
hr 14.5 91.96% 94.72%
hr 14.7 92.41 % 95.03%
hr 14.8 92.95% 95.62%
hr 15.0 93.04% 95.76%
hr 15.2 93.64% 96.34%
hr 15.3 93.85% 96.57%
hr 15.5 94.05% 96.79%
hr 15.7 94.43% 97.07%
hr 15.8 94.77% 97.31 hr 16.0 95.08% 97.59%
hr 16.2 95.59% 98.03%
hr Time Floatin Trian TPAM 24m HPLC
1e 24 m 16.3 95.47% 98.12%
hr 16.5 95.84% 98.55%
hr 16.7 96.13% 98.71 hr 16.8 96.24% 98.98%
hr 17.0 96.36% 99.09%
hr 17.2 96.75% 99.42%
hr 17.3 96.92% 99.62%
hr 17.5 97.33% 100.14%
hr 17.7 97.43% 100.27%
hr 17.8 97.61 % 100.26%
hr 18.0 97.74% 100.37%
hr 18.2 97.98% 100.68%
hr 18.3 98.32% 101.17%
hr 18.5 98.43% 101.22% 98.09%
hr 18.7 98.46% 101.20%
hr 18.8 98.59% 101.44%
hr 19.0 98.54% 101.29%
hr 19.2 98.87% 101.77%
hr 19.3 99.24% 101.77%
hr 19.5 99.37% 102.07%
hr 19.7 99.47% 102.26%
hr 19.8 99.68% 102.34%
hr 20.0 99.75% 102.53%
hr 20.2 99.86% 102.50%
hr 20.3 99.65% 102.53%
hr 20.5 100.08% 102.66%
hr 20.7 '100.13% 103.08%
hr 20.8 100.20% 103.00%
hr 21.0 100.27% 103.17%
hr 21.2 100.61 % 103.43%
hr 21.3 100.58% 103.64%
hr 21.5 100.70% 103.42%
hr 21.7 100.80% 103.55%
hr 21.8 100.75% 103.61 hr 22.0 101.08% 103.81 hr 22.2 100.84% 103.74%
hr 22.3 101.23% 104.04%
hr 22.5 101.22% 104.21 hr 22.7 101.43% 104.07%
hr 22.8 101.54% 104.34%
hr 23.0 101.72% 104.57%
hr 23.2 101.50% 104.47%
hr 23.3 101.76% 104.69%
hr 23.5 101.93% 104.63%
hr 23.7 101.74% 104.46%
hr 23.8 101.98% 104.84%
hr 24.0 102.08% 104.94% 101.67%
hr ~
WO 01/16582 PCT/ITS00l23800 Table 7: HHCR 16 mg Time Floatin Trian TPAM 16m HPLC
1e Method 0.0 0.34% -0.03%
hr 0.2 5.76% 6.96%
hr 0.3 7.50% 8.60%
hr 0.5 8.59% 10.10%
hr 0.7 9.72% 11.24%
hr 0.8 10.97% 12.19%
hr 1.0 12.14% 13.54% 10.27/
hr 1.2 13.38% 14.82%
hr 1.3 14.71 % 16.00%
hr 1.5 15.39% 16.84%
hr 1.7 16.81 % 18.12%
hr 1.8 17.99% 19.15%
hr 2.0 18.94% 20.15% 17.97/
hr 2.2 19.95% 21.12%
hr 2.3 21.20% 22.41 hr 2.5 22.15% 23.40%
hr 2.7 23.32% 24.36%
hr 2.8 24.47% 25.56%
hr 3.0 25.55% 26.76%
hr 3.2 26.81 % 27.83%
hr 3.3 27.71 % 28.56%
hr 3.5 28.78% 29.90%
hr 3.7 29.81 % 30.80%
hr 3.8 30.82% 31.92%
hr 4.0 31.86% 32.80% 30.99%
hr 4.2 32.76% 33.50%
hr 4.3 33.86% 34.70%
hr 4.5 34.77% 35.76%
hr 4.7 35.89% 36.84%
hr 4.8 36.56% 37.32%
hr 5.0 37.66% 38.63%
hr 5.2 38.49% 39.62%
hr 5.3 39.28% 40.30%
hr 5.5 40.20% 41.21 hr 5.7 41.43% 42.27%
hr 5.8 41.99% 43.06%
hr 6.0 43.13% 43.89%
hr 6.2 43.95% 44.68%
hr 6.3 44.84% 45.65%
hr 6.5 45.80% 46.64%
hr 6.7 46.61 % 47.48%
hr 6.8 47.53% 48.43%
hr 7.0 48.01 % 48.94%
hr 7.2 49.11 % 49.80%
hr 7.3 49.78% 50.84%
hr 7.5 ~ 50.48% 51.30%
hr WO 01/16582 PCT/US00lZ3800 Time Floatin Trian TPAM 16m HPLC
1e Method 7.7 51.41 % 52.49%
hr 7.8 52.23% 52.93%
hr 8.0 52.88% 53.59%
hr 8.2 53.94% 54.56%
hr 8.3 54.41 % 55.30%
hr 8.5 55.28% 56.02%
hr 8.7 56.11 % 56.89%
hr 8.8 56.93% 57.69%
hr 9.0 57.39% 58.04%
hr 9.2 58.29% 59.08%
hr 9.3 58.92% 59.85%
hr 9.5 59.71 % 60.53%
hr 9.7 60.33% 61.16%
hr 9.8 60.92% 61.78%
hr 10.0 61.53% 62.61 hr 10.2 62.44% 63.23%
hr 10.3 63.01 % 63.87%
hr 10.5 63.81 % 64.51 hr 10.7 64.33% 64.92%
hr 10.8 65.16% 65.91 hr 11 65.28% 66.10%
.0 hr _ 66.35% 66.87%
_ 11.2 hr 11.3 67.01 % 67.86%
hr 11.5 67.40% 68.17%
hr 11.7 68.38% 69.05%
hr 11 68.64% 69.23%
.8 hr _ 69.18% 6g.98%
12.0 hr 12.2 70.12% 70.71 hr 12.3 70.42% 71.30%
hr 12 71.20% 71.86%
.5 hr _ 71.75% 72.57%
12.7 hr 12.8 ?2.29% 73.01 hr 13.0 72.80% 73.28%
hr 13.2 73.33% 74.02%
hr 13.3 73.78% 74.59%
hr 13.5 74.61 % 75.03%
hr 13.7 74.99% 75.87%
hr 13.8 75.43% 76.09%
hr 14.0 76.02% 76.74%
hr 14.2 76.63% 77.27%
hr _ 76.91 % 77.51 14.3 hr 1 77.60% 78.33% - -4.5 hr _ 77.76% 78.84%
14.7 hr 14.8 78.16% 78.99%
hr 15.0 78.79% 79.40% -hr- -15.2 __ 79.87%
hr 79.08%
15.3 79.79% 80.31 hr 15.5 80.10% 80.84%
hr ~5 Time Floatin Trian TPAM 16m HPLC
1e Method 15.7 80.72% 81.26%
hr 15.8 80.88% 81.63%
hr 16.0 81.30% 82.15% 84.33%
hr 16.2 81.61 % 82.33%
hr 16.3 82.06% 82.63%
hr 16.5 82.32% 82.93%
hr 16.7 82.94% 83.68%
hr 16.8 83.28% 83.70%
hr 17.0 83.65% 84.04%
hr 17.2 83.95% 84.65%
hr 17.3 84.27% 85.21 hr 17.5 84.89% 85.62%
hr 17.7 85.13% 86.04%
hr 17.8 85.55% 86.05%
hr 18.0 86.14% 86.79% 89.09%
hr 18.2 86.59% 87.22%
hr 18.3 86.88% 87.39%
hr 18.5 87.37% 87.83%
hr 18.7 87.64% 88.28%
hr 18.8 _ . ..88.07% . 88.93% .
hr .
19.0 88.71 % 89.38%
hr 19.2 88.99% 89.67%
hr 19.3 89.15% 89.96%
hr 19.5 89.27% 89.98%
hr 19.7 89.84% 90.60%
hr 19.8 90.13% 90.82%
hr 20.0 90.45% 91.47%
hr 20.2 ~ 90.70% 91.37%
hr 20.3 hr 20.5 91.59% 92.25%
hr 20.7 91.27% 92.13%
hr 20.8 91.53% 92.73%
hr 21.0 91.86% 92.59%
hr 21.2 92.18% 92.97/u hr 21.3 92.46% 93.35%
hr 21.5 92.66% 93.58%
hr 21.7 ' 92.78% 93.79%
hr 21.8 93.01 % 94.09%
hr 22.0 93.12% 94.10%
hr 22.2 93.49% 94.72%
hr 22.3 93.44% 94.78%
hr 22.5 93.36% 94.54%
hr 22.7 94.05% 95.08%
hr 22.8 94.09% g5.37%
hr 23.0 94.36% 95.34%
hr 23.2 94.57% 95.55%
hr 23.3 94.57% 95.65%
hr 23.5 94.77% 96.24%
hr yG
Time Floatin Trian 1e TPAM 16m HPLC
Method 23.7 95.04% 96.19%
hr 23.8 - 95.26% 96.69%
hr 24.0 95.08% 96.48% 97.67%
hr Table 8: HHCR 32 mg Time Floatin Trian 1e TPAM 32m HPLC
Method 0.0 0.36% 0.11 hr 0.2 6.08% 6.60%
hr 0.3 7.75% 8.64%
hr-0.5 9.00% 9.68%
hr 0.7 10.13% 10.86%
hr 0.8 11.29% 12.22%
hr 1.0 12.53% 13.42% 11.07%
hr 1.2 13.71 % 14.60%
hr 1.3 14.95% 15.84%
hr 1.5 16.07% 16.93%
hr 1.7 17.25% 18.23%
hr 1.8 18.33% 19.38%
hr 2.0 19.52% 20.49% 18.94%
hr 2.2 20.57% 21.60%
hr 2.3 21.73% 22.77%
hr 2.5 22.83% . .- 23.81%
hr ..
-2.7 24.04% 25.11 hr 2.8 24.98% 26.18%
hr 3.0 26.14% 27.03%
hr 3.2 27.16% 28.16%
hr 3.3 28.24% 29.29%
hr -3.5 29.22% 30.33%
h~--3.7 30.32% 31.33%
hr 3.8 31.21 % 32.29%
hr 4.0 32.39% 33.46% 31.34%
hr 4.2 33.13% 34.17%
hr 4.3 34.01 % 35.13%
hr 4.5 35.06% 36.05%
hr 4.7 36.03% 37.11 hr 4.8 37.02% 38.20%
hr 5.0 37.84% 39.14%
hr 5.2 38.82% 39.86% -.
hr 5.3 39.70% 40.86%
hr 5.5 40.61% 41.71%
hr 5.7 41.60% 42.59%
hr 5.8 42.35% 43.65%
hr 6.0 43.26% 44.43%
hr 6.2 44.05% 45.21 hr 6.3 44.94% 46.10%
hr 6.5 45.81 % 47.02%
hr WO 01/16582 PCT/US00lZ3800 Time Floatin Trian 1e TPAM 32m HPLC
Method 6.7 46.69% 48.04%
hr 6.8 47.55% 48.76%
hr 7.0 48.27% 49.63%
hr 7.2 49.23% 50.45%
hr 7.3 50.01% 51.21%
hr 7.5 50.66% 51.95%
hr 7.7 51.57% 52.75%
hr 7.8 52.41 % 53.66%
hr 8.0 53.05% 54.51 hr 8.2 53.76% 55.05%
hr 8.3 54. 56.03%
hr 74%
8.5 _ 56.52%
hr 55.38%
8.7 56.08% 57.39%
hr 8.8 56.95% 58.18%
hr 9.0 57.69% 58.84%
hr 9.2 58.38% 59.55%
hr 9.3 59.14% 60.47 hr %
9.5 59.71 % -. _ _ -hr - 60.78%
9.7 ..:. 6.49% - - 81.64% -hr 9.8 61.10% 62.49%
hr 10.0 61.7 63.23%
hr 6%
- 10.2 _ 8% -.
hr-- ..... 62.45% 83.8 10.3 -63.07% -. - _ hr x.58%
10.5 63.84% 65.47%
hr 10.7 64 65.99 hr .4 %
5%
_ _ _ 10.8 _ - 86.64%
hr -. --85.08%--.
11.0 65.64% 67.24%
hr 11.2 _ ... 66:49% 88.01 hr 11.3 66.95% 68.41 hr 11.5 67.55% 69.24%
hr 11.7 68.13% 69.74%
hr 11.8 68.83% 70.29%
hr 12.0 69.36% 71.07%
hr 12.2 70.04% 71.57%
hr 12.3 70.65% 72.26%
hr 12.5 71.24% 72.71 hr 12.7 71:73% 73.28%
hr 12.8 72.33% 73.95%
hr 13.0 72.91 % 74.43%
hr 13.2 73.38% 75.08%
hr 13.3 73.88% 75.65%
hr 13.5 .. .. 74:50% 76.07%
hr 13.7 75.12% 76.72%
hr 13.8 75.53% 77.25%
hr 14.0 76.05% 77.70%
hr 14.2 76.62% 78.23%
hr 14.3 77.18% 78.86%
hr 14.5 77.70% 79.45%
hr y~
Time Floatin Trian TPAM 32m HPLC
1e Method 14.7 78.17% 79.96%
hr 14.8 78.63% 80.56%
hr 15.0 79.01 % 80.82%
hr 15.2 79.48% 81.36%
hr 15.3 79.95% 81.75%
hr 15.5 80.59% 82.54%
hr 15.7 81.01 % 82.64%
hr 15.8 81.25% 83.00%
hr 16.0 81.75% 83.55% 84.73%
hr 16.2 82.10% 83.94%
hr 16.3 82.45% 84.35%
hr 16.5 83.04% 84.90%
hr 16.7 83.39% 85.24%
hr 16.8 83.78% 85.65%
hr 17.0 84.17% 86.04%
hr 17.2 84.55% 86.49%
hr 17.3 85.03% 86.91 hr 17.5 85.45% 87.30%
hr 17.7 85.76% 87.72%
hr 17.8 86.15% 87.96%
hr 18.0 86.60% 88.55% 89.49%
hr 18.2 86.89% 88.66%
hr 18.3 87.31 % 89.04%
hr 18.5 87.58% 89.29%
hr 18.7 88.06% 89.83%
hr 18.8 88.48% 90.16%
hr 19.0 88.87% 90.37%
hr 19.2 89.17% 90.75%
hr 19.3 89.43% 90.99%
hr 19.5 89.87% 91.47%
hr 19.7 90.23% 91.84%
hr 19.8 90.49% 91.96%
hr 20.0 90.63% 92.18%
hr 20.2 91.06% 92.55%
hr 20.3 91.18% 92.91 hr 20.5 91.48% 92.93%
hr 20.7 91.64% 93.32%
hr 20.8 92.10% 93.58%
hr 21.0 92.37% 93.89%
hr 21.2 92.42% 93.94%
hr 21.3 92.79% 94.23%
hr 21.5 92.93% 94.44%
hr 21.7 93.04% 94.57%
hr 21.8 93.28% 94.82%
hr 22.0 93.59% 95.30%
hr 22.2 93.61 % 95.34%
hr 22.3 94.01 % 95.57%
hr 22.5 94.10% 95.90%
hr WO 01/16582 CA 02383906 2002-02-27 pCT/US00/23800 Time Floatin Trian 1e TPAM 32m HPLC
Method 22.7 94.40% 96.02%
hr 22.8 94.46% 96.15%
hr 23.0 94.65% 96.19%
hr 23.2 94.88% 96.52%
hr 23.3 95.09% 96.82%
hr 23.5 95.28% 96.93%
hr 23.7 95.50% 97.04%
hr 23.8 95.70% 97.14%
hr 24.0 ~ - - 95.80% 97.52% 98.72%
hr Second Order Derivative Spectral Analysis Method In accordance with an embodiment of the present invention, scattering problems associated with in situ dissolution methods are reduced by calculating a second derivative of the spectra, subtracting an initial noise offset from the second derivative. The resultant difference value is then proportional to the amount of analyte dissolved. In order to obtain a plot of percent active agent dissolved versus time, the second derivative of the LJV spectra of the dissolution bath is first calculated.
The derivative of the spectra at a given point (i) is estimated by determing the slope of a straigth line which interconnects a previous spectral data point (i-1) and a next spectral data point (i+1). As shown in Figure 21, this line approximates the derivative at that point because the slope of the line between the points (i-1) and (i+1) is nearly the same (parallel) to the tangent line at the spectral data point (i).
Therefore, as shown in Figure 22, the derivative at any given point in the spectra can be estimated by calculating the slope between the previous data point and the next data point. This slope between two points can be more easily expressed as SLOPE = (y2-yl) .
(x2 - x1) Turning to Figure 22, the derivative of the point (284nm) is calculated by the equation Derivative@284nm = Absorbance@286nm-Absorbance@282nm . den this calculation is 286nm - 282nm carried out for each data point of the spectral plot, the derivative of the spectra is generated as shown in Figure 23.
5b rcT~rsoon3soo In accordance with the present invention, a second derivative of the spectra is taken in order to to correct for scattering. Since the second derivative represents the rate of change of the rate of change of the function, it will only represent spectral characteristics where a peak is present. Since the scattering interference causes a baseline offset with a variable slope, the second derivative removes this interference. By integrating the area under (and above) the second derivative, using a trapezoidal approximation, a value that is characteristic of the amount of analyte in the scattering matrix can be developed.
In order to correct for system noise, an initial noise offset is subtracted from the plot of the second order derivative of the spectral plot. The initial noise offset is set equal to the value of the second order derivative at a time t=0, which is a time just before the sample is placed in the dissolution vessel.
Example 7 In order to demonstrate that the method in accordance with the present invention provides a spectral plot that is largely unaffected by scattering interference, the scattering of a pharmaceutical matrix was simulated by using a photometric standard (turbidity standard) to create an interferance in the spectral observation of a dilute tramadol HCl solution. This experiment was performed using an HP 8452A PDA Spectrophotometer manufactured by Hewlett Packard as the CCD. This Spectrophotometer is a card-type CCD which is mounted within a PCB slot in a computer equipped with a Pentium~ processor.
The experiment was conducted by scanning a dilute tramadol standard, and then adding small amounts of turbidity standard to the sample between scans. The resultant W spectra shown in Figure 24 are typical for a drug substance in the presence of a scattering matrix (polymer).
The data set forth below in tables 9, 10, 11, and 12 regarding the turbidity interference results in the analysis of Tramadol HCL for 0, 1, 2, and 3 drops of turbidity standard respectively are plotted in Figure 24.
TABLE 9: 0 drops of turbidity standard Wavelen th nm Absorbance AU
220 3.41 E-01 222 3.20E-01 224 2.88E-01 226 2.52E-01 228 2.07E-01 230 1.56E-01 232 1.06E-01 234 6.52E-02 236 3.79E-02 238 2.29E-02 240 1.62E-02 242 1.41 E-02 244 1.40E-02 246 1.50E-02 248 1.68E-02 250 1.91 E-02 252 2.22E-02 254 2.59E-02 256 3.09E-02 258 3.67E-02 260 4.33E-02 262 5.12E-02 264 5.99E-02 266 6.77E-02 268 7.56E-02 270 8.45E-02 272 8.97E-02 274 8.71 E-02 276 8.30E-02 278 8.22E-02 280 7.36E-02 282 5.28 E-02 284 3.07E-02 286 1.69E-02 288 1.07E-02 290 8.10 E-03 292 7.13E-03 294 6.61 E-03 296 6.52E-03 298 6.42E-03 300 6.30E-03 TABLE 10: 1 drop of turbidity standard Wavelen th nm Absorbance AU
220 0.621536 Wavelen th nm Absorbance AU
222 0.601105 224 0.57312 226 0.53894 228 0.491302 230 0.430893 232 0.368729 234 0.315384 236 0.27504 238 0.24736 240 0.228699 242 0.215378 244 0.204971 246 0.196899 248 0.190292 250 0.185272 252 0.181839 254 0.179779 256 0.179779 258 0.180923 260 0.183319 262 0.187653 264 0.192978 266 0.197342 268 0.201492 270 0.206879 272 0.209381 274 0.20253 276 0.19426 278 0.189087 280 0.176407 282 0.152115 284 0.126846 286 0.10997 288 0.100723 290 9.53E-02 292 g.16E-02 294 8.85E-02 296 -- g_60E-02 -298 - 8.37E-02 300 8.15E-02 TABLE 11: 2 drops of turbidity standard Wavelen th nm Absorbance AU
220 1.0013 222 0.982758 224 0.960892 WO 01/16582 CA 02383906 2002-02-27 pCT/pS00/23800 Wavelen th nm Absorbance AU
226 0.933365 228 0.884766 230 0.814987 232 0.739136 234 0.669495 236 0.612488 238 0.568283 240 0.533356 242 0.504379 244 0.479553 246 0.458557 248 0.440186 250 0.424911 252 0.412064 254 0.40155 256 0.394394 258 0.388809 260 0.38504 262 0.384399 264 0.385147 266 0.38446 268 0.383331 270 0.383667 272 0.382248 274 0.36972 276 0.355362 278 0.101 280 0.325882 282 0.296631 284 0.267014 286 0.245743 288 0.232315 290 0.222961 292 0.215332 .294 0.208725 296 0.202652 298 0.197205 300 0.192017 TABLE 12: 3 drops of turbidity standard Wavelen th nm Absorbance AU
220 1.33568 222 1.32117 224 1.30655 226 1.28862 228 1.24454 Wavelen th nm Absorbance AU
230 1.17163 232 1.08739 234 1.00568 236 0.935791 238 0.877228 240 0.828064 242 0.785416 244 0.748138 246 0.715591 248 0.68631 250 0.661438 252 0.640198 254 0.621689 256 0.607681 258 0.595795 260 0.586044 262 0.580704 264 0.576675 266 0.571274 268 0.565384 270 0.560547 _ 0.55574 -274 0.537399 _. :. 276- - 0.517441 278 0.500427 280 0.476944 282 0.443085 284 0.409012 286 0.383759 288 0.366577 290 0.353027 292 0.341568 294 0.331436 296 0.322189 298 0.313507 _ 0.305374 The amount of analyte was then quantitated using two methods, a standard single point baseline correction, and a 2°d derivative function in accordance with the present invention. The results are sumarized in the table below .
Amount of Turbidity Baseline Subtraction Area of f'(x) Standard 272 nm - 304 nm 0 dro 0.083 0.018 1 dro 0.132 _ 0.018 2 dro 0.200 0.018 3 dro 0.266 0.018 D 46.81 % 0.90 The data in Table 13 demonstrates that the second derivative method in accordance with the present invention provides values that are largely unaffected by how much turbidity standard is added, as is demonstrated by the very low RSD (relative standard deviation). As one of skill in the art will appreciate, a low RSD value (i.e., standard deviation/avg. of values) indicates that there is very little deviation between the measured values despite the change in turbidity. In contrast, the RSD for the baseline subtraction method is significantly greater, indicating that the turbidity of the solution has a much greater affect on measured values. This is significant, because it is desirable to accurateiy quantify the amount of drug dissolved in the dissolution media in a dynamic matrix enviroment, in this case, a sample submerged in a dissolution medium replete with the debris from the partially dissolved sample.
It should be noted, however, that the matrix interference in this experiment is simplifed considerably due to the fact that the particle size of the polymer is uniform.
In an actual dissolution, the polymer size would be quite variable. Nevertheless, this test indicates that the second order derivative methods are significantly less affected by turbidity than a conventional baseline subtraction method.
As one of ordinary skill in the art will appreciate, a variety of programs known in the art can be used to calculate a second derivative, or can be readily programed by a computer programmer. In fact, the HP 8452A PDA spectrophotometer described above includes a built in function that could alternatively be used to calculate the first and second derivative of an acquired spectrum.
Example 8 In order to evaluate the effectiveness of the present invention in an actual dissolution vessel, dissolution data obtained by the HPLC method is compared with dissolution data obtained in situ in accordance with the present invention in Figure 25. The HPLC data is the same data referenced above in connection with Example 6. The in situ data used was generated in the same manner as the data referenced above in connection with Example 6.
The dissolution data obtained by the HPLC method at 1 , 2, 12, 18, and 24 hours in the manner set forth above is plotted again in Figure 25. Figure 25 also shows a plot of a second order derivative of the in-situ generated spectrum over a period from 0 to 24 hours, sampled every 10 minutes. As shown in Figure 25, the second order derivative function exhibits an initial offset at t=0 , which is a time just before the dosage unit is added to the vessels. This initial dissolved deviation is the result of the integration of the initial noise of the system, which is enhanced significantly by the 2°d derivative calculation. In the particular example in Figure 25, the initial value is approximately 3% at time t = 0.
In accordance with the present invention, this initial noise offset (the 2°d derivative of the value of the spectra at t = 0) is subtracted from all future measurements, so that the curve will correlate well with the HPLC sampling data. This corrected 2°d derivative was then used to recaculate both the accuracy and precision experiments for the 12 mg and 24 mg hydromorphone HPLC data set forth above.
Figure 26 shows an intermediate precision plot of the 12 mg hydromorphone capsule described above. Plots T1 and T2 are both plots of the dissolution of the 12 mg capsule described above conducted in situ with the equipment described above. In fact, T1 was generated from the same spectral data as the in situ plots of Figure 17.
However, T1 and T2 are derived from data generated by different technicians performing identical measurements on the same apparatus on different days. The data was then processed according to the floating triangle method to produce plots T1 and T2.
Figure 27 shows also shows an intermediate precision plot of the 12 mg hydromorphone capsule as described above. Plots T1' and T2' were generated with the 2d derivative baseline corrected method from the identical spectral data as plots T1 and T2, respectively. As plots T1' and T2' were generated from the same data as plots T1 and T2 respectively, the differences between the plots of Figures 26 and 27 are due solely to the different processing methods. A
comparison of Figures 26 and 27 clearly demonstrates that the plots generated with the baseline corrected second derivative method are at least as reproducible as the plots of the same data with the floating triangle method.
Figures 28 and 29 similarly show intermediate precision plots of the in situ dissolution of the 24 mg hydromorphone capsule described above. The spectral data was generated in the same manner as described above with respect to Example 6. As with Figure 26, plots T3 and T4 in Figure 28 were derived from data generated by different technicians performing identical measurements on the same apparatus on different days, and the data was processed according to the floating triangle method to produce plots T3 and T4. Plots T3' and T4' in Figure 29 were generated with the 2d derivative baseline corrected method from the identical spectral data as plots T3 and T4 of Figure 28, respectively. A comparison of Figures 28 and 29 demonstrates that the plots generated with the baseline corrected second derivative method are at least as reproducible as the plots of the same data with the floating triangle method.
Figure 30 illustrates a 12 mg accuracy validation which compares HPLC data generated as described in Example 6 with plots T1 (floating triangle method) and T1' (baseline corrected 2d derivative method). Figure 31 similarly illustrates a 24 mg accuracy validation which compares the HPLC data with plots T3 and T3' in Figures 28 and 29, respectively. Both Figure 30 and Figure 31 demonstrate that the baseline corrected 2d derivative method more closely correlates to the HPLC data.
The underlying data for Figures 25, 30, and 31 with regard to the baseline corrected second derivative plot is set forth below in Tables 14 and 15:
Table 14 Time Baseline CorrectionBaseline Corrected 12m 2nd Deriv 0.0 -1.58% 0.00%
hr 0.2 7.36% 5.62%
hr 0.3 10.87% 8.84%
hr 0.5 12.66% 10.78%
hr Time Baseline CorrectionBaseline Corrected 12m 2nd Deriv 0.7 hr 14.30% 12.61 0.8 hr 15.66% 13.74%
1.0 hr 17.23% 15.23%
1.2 hr 18.71 % 16.63%
1.3 hr 20.03% 18.05%
1.5 hr 21.39% 19.24%
1.7 hr 22.76% 20.71 1.8 hr 24.08% 21.95%
2.0 hr 25.46% 23.39%
2.2 hr 26.75% 24.71 2.3 hr 28.49% 26.11 2.5 hr 30.19% 27.22%
2.7 hr 31.58% 27.87%
2.8 hr 32.86% 29.50%
3.0 hr 33.94% 30.61 3.2 hr 35.63% 31.83%
3.3 hr 35.99% 32.31 3.5 hr 37.17% 33.56%
3.7 hr 38.38% 34.56%
3.8 hr 39.58% 36.12%
4.0 hr 40.83% 37.02%
4.2 hr 42.20% 38.31 4.3 hr 43.42% 39.21 4.5 hr 44.70% 40.19%
4.7 hr 45.93% 41.25%
4.8 hr 47.14% 42.24%
5.O hr 46.75% 43.34%
5.2 hr 47.48% 43.88%
5.3 hr 48.46% 45.29%
5.5 hr _ .49.88% 46.53%--5.7 hr 51.10% 47.26%
5.8 hr 52.29% 47.91 6.0 hr 53.57% 49.20%
6.2 hr 54.65% 50.21%
6.3 hr 55.78% 1.04 %
6.5 hr 56.87% _ _ 52.22%
6.7 hr 58.00% 53.05%
6.8 hr 59.03% 54.11 7.0 hr 60.01 % 55.16%
7.2 hr 61.08% 56.02%
7.3 hr 61.99% 57.00%
7.5 hr 63.12% 58.17%
7.7 hr 64.31 % 59.07%
7.8 hr 65.31 % 60.01 8.0 hr 66.19% 60.36%
8.2 hr =66.77% 61.78% -8.3 hr 67.31 % 62.29%
8.5 hr 68.28% 63.83%
Time Baseline CorrectionBaseline Corrected 12m 2nd Deriv 8.7 hr 69.47% 64.08%
8.8 hr 70.56% 64.83%
9.0 hr 71.85% 65.90%
9.2 hr 72.91 % 66.45%
9.3 hr 73.75% 67.11 9.5 hr 74.73% 67.90%
9.7 hr 75.63% 68.76%
9.8 hr 76.20% 69.89%
10.0 77.33% 70.42%
hr 10.2 78.69% 70.86%
hr 10.3 80.03% 71.83%
hr 10.5 80.88% 72.62%
hr 10.7 81.90% 73.05%
hr 10.8 82.96% 73.65%
hr 11.0 83.60% 74.26%
hr 11.2 83.89% 75.35%
hr 11.3 84.66% 76.36%
hr 11.5 85.16% 76.46%
hr 11.7 85.62% 77.48%
hr 11.8 86.19% 77.71 hr 12.0 87.13% 78.84%
hr 12.2 ~ 87.78% 79.23%
hr 12.3 88.79% 79.80%
hr 12.5 89.90% . $p.32%
hr 12.7 ~ 90.59% 80.50%
hr 12.8 91.40% 81.43%
hr 13.0 92.08% 81.79%
hr 13.2 92.92% 82.08%
hr 13.3 __ 83.41 hr 92.77%
13.5 92.71 % 83.86%
hr 13.7 92.90% 83.99%
hr 13.8 93.12% 84.90%
hr 14.0 93.71 % 85.66%
hr ~4.2 - 94.24% 85.88%
hr -14.3 94.81 % 85.99%
hr 14.5 95.36% 86.58%
hr 14.7 95.59% 87.11 hr 14.8 95.97% 87.31 hr 15.0 96.43% 88.13%
hr 15.2 97.01 % 88.08% -_ hr 15.3 87.36% 88.41 hr 15.5 97.84% 88.75% -hr 15.7 98.27% 89.26%
hr 15.8 98.60% 89.68% _ _ hr 16.0 99.04% 89.99/0 hr 16.2 99.17% 90.50%
hr _ 16.3 99.46% 90.30%
hr ~6.5 ~ 100.04% 90.80% -hr Time Baseline CorrectionBaseline Corrected 12m 2nd Deriv 16.7 100.21 % 91.23%
hr 16.8 100.41 % 91.54%
hr 17.0 100.85% 91.74%
hr 17.2 101.10% 92.17%
hr 17.3 101.43% 92.10%
hr 17.5 101.77% 92.64%
hr 17.7 101.95% 92.78%
hr 17.8 102.04% 93.34%
hr 18.0 102.50% 93.85%
hr 18.2 102.67% 93.51 hr 18.3 102.87% 93.69%
hr 18.5 103.09% 93.95%
hr 18.7 103.20% 94.00%
hr 18.8 103.31 % 94.26%
hr 19.0 103.87% 94.31 hr 19.2 104.03% 94.76%
hr 19.3 104.16% 94.81 hr 19.5 104.62% 95.16%
hr 19.7 104.75% 94.86%
hr 19.8 105.00% 95.27%
hr 20.0 105.18% 95.81 hr 20.2 ~ 105.61 % 95.62 hr %
20.3 -105.95% _ hr 95.94%-20.5 106.11 % 96.00%
hr 20.7 106.09% 96.34%
hr 20 -106.42% 96.76%
.8 hr _ 106.54% 96.82%
21.0 hr 21.2 106.82% 96.78%
hr 21.3 107.04% 96.73%
hr 21.5 107.25% 97.06%
hr 21.7 --107.46% _ hr 97.07% _.
21.8 107.62% 97.03%
hr 22.0 107.80% 96.99%
hr 22.2 108.09% 97.11 hr 22.3 108.18% 98.16%
hr 22.5 108.16% 97.53%
hr 22. . -108.03% gg.02%
7 hr _ ~ ~ 08.32% 97.95%
22.8 hr 23.0 108:69% 97.75%
hr 23.2 :108:71 % 98.07%
hr 23.3 108.92% 98.94%
hr 23.5 1-8.81 % 98.04%
hr 23.7 109.12% 98.44%
hr 23.8 109.16% 98.20%
hr 24.0 109.48% 98.46%
hr Table 15 Time Baseline CorrectionBaseline Corrected 24m 2nd Deriv 0.0 hr 0.06% 0.00%
0.2 hr 7.27% 6.86%
0.3 hr 9.58% 9.36%
0.5 hr 11.22% 10.59%
0.7 hr 12.69% 12.30%
0.8 hr 14.14% 13.42%
1.0 hr 15.45% 14.99%
1.2 hr 16.78% 16.12%
1.3 hr 18.03% 17.17%
1.5 hr 19.17% 18.65%
1.7 hr 20.40% 19.87%
1.8 hr 21.55% 21.02%
2.0 hr 22.78% 22.03%
2.2 hr 23.91 % 23.42%
2.3 hr 25.11 % 24.71 2.5 hr 26.39% 25.76%
2.7 hr 27.47% 27.05%
2.8 hr 28.71 % 28.34%
3.0 hr 29.86% 29.47%
3.2 hr 31.08% 30.99%
3.3 hr ~ 32.23% 31.99%
3.5 hr 33.46% 33.01 3.7 hr ~.~% 34.32%
3.8 hr 35.86% 35.44%
4.0 hr 37.03% 36.82%
4.2 hr 38.24% 37.96%
4.3 hr 39.42% 39.16%
4.5hr 40.66% 40.64%
4.7 hr 41.74% 41.72%
4.8 hr - 42.99% 42.79 %
5.0 hr 43.96% _ 44.2 3%
5.2 hr 45.16% _ 45.47%
5.3 hr 46.31 % 46.63%
5.5 hr = 47.62% 47.71 5.7 hr 48 49.17%
.66%
5.8 hr _ 50.23% -. _ 49.70%
6.0 hr 50.76% 51.28 %
6.2 hr . 51.94% _ 52.47% -6.3 hr 53.03% 53.44%
6.5 hr 54.06% 54.49%
6.7 hr 55.15% 55.66%
6.8 hr _ 56.23% . 56.64%
7.0 hr 57.26% 57.37%
7.2 hr 58.39% 58.39%
7.3 hr 59.43% 59.54%
7.5 hr 60.43% 60.40%
7.7 hr 61.42% 61.46%
7.8 hr 62.39% 62.72%
Time Baseline CorrectionBaseline Corrected 24m 2nd Deriv 8.0 hr .63.26% - 63.56%
8.2 hr 64.24% 64.52%
8.3 hr 64.93% 65.99%
8.5 hr 66.01 % 66.77%
8.7 hr 67.04% 67.44%
8.8 hr 67.98% 68.39%
9.0 hr 68.87% 69.17%
9.2 hr 69.64% 70.16%
9.3 hr 70.68% 71.18%
9.5 hr 71.41% 71.91%
9.7 hr 72.13% 72.65%
9.8 hr 72.87% 73.41 10.0 73.66% 74.25%
hr 10.2 74.32% 74.91 hr 10.3 75.30% 75.49%
hr 10.5 76.04% 76.06%
hr 10.7 76.77% 76.95%
hr 10.8 77.51 % 77.36%
hr 11.0 78.08% 77.90%
hr 11.2 78.70% 78.61 hr 11.3 79.28% 79.37%
hr .5 hr 79.86% 80.11 _ 80.39% 80.87%
11.7 hr 11.8 81.01% 81.56% -hr -12.0 - 81.46% 82.17% -hr -12.2 - 82.00% 82.89%
hr 12.3 -82.55% 3% -hr- 83.2 12.5 83.18% _ hr 83.49%.
12.7 ...$3.74% 83.82%
hr -12.8 84.18% 84.45%
hr 13.0 84.73% 85.30%
hr 13.2 85.15% 85.57%
hr 13.3 85.64% 85.70%
hr 13.5 85.92% 86.51 hr %
13.7 86.29% _ hr 86.77%
13.8 86.81 % 87.12%
hr 14.0 87.25% 88.13%
hr 14.2 87.57% 88.28%-hr 14.3 87.82% 88.93%
hr 14.5 88.16% 89.06%
hr 14.7 88.57% 89.39%
hr 14.8 88.88% 89.86% -hr 15.0 89.11 % 90.32%
hr 15.2 89.51 % 90.52%
hr 15.3 89.81 % 90.78%
hr 15.5 90.04% 91.08%
hr _ 15.7 90.24% 91.20%
hr 15.8 90.59% 91.42%
hr Time Baseline CorrectionBaseline Corrected 24m 2nd Deriv 16.0 90.94% 91.84%
hr 16.2 91.27% 92.12%
hr 16.3 91.35% 92.38%
hr 16.5 91.65% 92.73%
hr 16.7 91.88% 93.10%
hr 16.8 92.09% 93.30%
hr 17.0 92.35% 93.01 hr 17.2 92.64% 93.37%
hr 17.3 92.81 % 93.82%
hr 17.5 93.04% 93.92%
hr 17.7 93.15% 94.17%
hr 17.8 93.32% 94.48%
hr 18.0 93.56% 94.75%
hr 18.2 93.74% 94.71 hr 18.3 93.94% 95.20%
hr 18.5 .._..94,:U8% . g5.43%
hr 18.7 94.26% 95.34%
hr 18.8 94.43% 95.90%
hr 19.0 94.56% 95.46%
hr 19.2 94:68% 95.84%
hr 19.3 94.99% 95.98%
hr 19.5 95.14% 96.34%
hr 19.7 95.17% 96.39%
hr _ ~ 95.39% 96.59%
19.8 hr __ 95.52% 96.61 20.0 hr 20.2 95.68% 96.53%
hr 20.3 95.68% 97.16%
hr 20.5 95.96% 96.93%
hr 20.7 96.02% 97.25%
hr 20.8 96.16% 97.28%
hr 21.0 96.20% 97.32%
hr 21.2 96.46% . .. 87.42%
hr 21.3 , 86:48% 97.38%
hr 21.5 ~ 96.61 % 97.24%
hr 21.7 96.74% 97.56%
hr 21.8 96,81 % - -97.71 hr 22.0 96.94% 97.77%
hr 22.2 96.91 % 97.85%
hr 22.3 97.08% 98.16%
hr 22.5 97.12% gg.31%
hr 22.7 97. 98.12 hr 22% - %
22.8 _ _ hr 87:38% -- 88.33% - _.
23.0 , .:97.47% 98.57% - _ hr 23.2 97.46% 98.37%
hr 23.3 97.54% 98.46% -hr 23.5 97.71 % 98.64%
hr 23.7 97.68% g8.55%
hr 23.8 ' 97:78% ~ 98.67% _ hr Time~Baseline Correction 24mg I Baseline Corrected 2nd Deriv I
I 24.0 hr ~ 97.85% I 98.75%
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 S encompassed within the appended claims.
-21 es.a ee.7 Io,a e7.e Nn 21.s 11.2 Ie.e e1.4 Ie.o ND
2x a.4 17.9 a2. o Ie.e ND
2s.s 17.4 1e.4 e2. e ea.s ND
xa 11.D Ie.t aa. a ss.e No 2a.s Ie.e ILO aa. s ao.5 No 24 Ia.4 ea.a a4. 4 st.2 n.4 I4,a 19.7 11.6 a5. 1 f 1.a NO
25 90.a 9e. 5 92.1 ND
90.5 The table clearly demonstrates that the in-situ dissolution system gives results that are precise and that correlate well to the HPLC method. Figure 4 shows the plot of the average dissolution of three tablets and the results from the HPLC method.
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 about every 2.5 seconds. The absorption at a pre-selected wavelength is plotted against time to generate a dissolution profile. Figure 5 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 such information.
Ezample 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 l, by using TableCurve 2D
program, one can fit the dissolution data into the equation as shown in Figure 6. On top of Figure 6, the best-fit equation for the data is displayed.
If one uses the 12-hour data, at 1-hour intervals and fits them to the best-fit equation, the dissolution profile generated would be as shown in Figure 7. When 16-hour data, taken at 1-hour interval, are taken to find the best-fit equation, it produced the curve of Figure 8. Note that this curve is closer to 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.
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.
Ezample 5 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 path length (20mm), a 24-hour dissolution profile is generated for hydromorphone HCl 12 mg that is comparable to that obtained from a validated HPLC method. Results are displayed in Table 3 and Figure 10.
Table 3. Data of Hydromorphone HCl 12 mg Capsule Dissolution Fiber Optics v. HPLC
Hydromorphone d HCI
Dissolve HourFiberHPLCHourFiberHPLCHourFiberHPLCHourFiberHPLC
0 1.7 0 0.172.76 6.1738.9 12.262 18.1779 0.335 6.3339.2 12.362.5 18.3379.7 0.57.18 6.540 12.563.2 18.579.8 0.678.67 6.6740.6 12.763.7 18.6780.2 0.8310 6.8341.5 12.864.4 18.8380.5 t 11.411.37 42.2 13 64.9 19 80.8 1.1712.5 7.1743 13.265.5 19.1781.2 1.3313.7 7.3343.5 13.366 19.3381.6 1.514.8 7.544.2 13.566.4 19.582 1.6716 7.6744.9 13.767 19.6782.1 1.8317.2 7.8345.7 13.867.5 19.8382.6 2 18.118.28 46.356 14 68 20 82.9 2.1719.3 8.1746.8 14.268.5 20.1782.9 2.3320.1 8.3347.2 14.369 20.3383.5 2.521.2 8.548.4 14.569.6 20.583.6 2.6721.8 8.6749.2 14.770.2 20.6784 2.8322.8 8.8349.6 14.870.7 20.8384.1 3 23.8 9 50.3 15 71.3 21 84.4 3.1724.7 9.1751.1 15.271.5 21.1784.6 3.3325.4 9.3351.8 15.372.1 21.3384.9 3.526.1 9.552.3 15.572.3 21.585.2 3.6726.9 9.6753.3 15.772.9 21.6785.4 3.8328 9.8353.7 15.873.4 21.8385.5 4 28.731.810 54.4 16 73.9 22 85.7 4.1729.7 10.255.1 16.274.3 22.1786.2 4.3330.5 10.355.9 16.374.8 22.3386.3 4.531.4 10.556.2 16.575.3 22.586.6 4.6732.2 10.757.1 16.775.6 22.6787.1 4.8332.8 10.857.3 16.875.8 22.8387.1 5 33.7 11 58 17 76.5 23 87.1 5.1734.4 t 58.6 17.276.9 23.1787.3 1.2 5.3335.3 11.359.1 17.377.4 23.3387.5 5.536 11.559.7 17.577.9 23.587.7 5.6736.7 11.760.2 17.777.9 23.6787.9 5.8337.5 11.860.9 17.878.4 23.8387.9 6 38.3 12 61.473.818 78.990.324 88.399.8 Svstem Design Figure 11 shows an illustrative system 1 in accordance with an embodiment of the present invenrion. The system 1 includes a computer 20, a display screen 10, a keyboard 40, and a mouse 30. A plurality (in this case seven) of CCD's (charge coupled devices) are coupled to the computer 20. In this regard, the CCD's can be stand-alone external CCD
spectrometers (connected to the computer 20 via, for example, a PCMIA card), or can be internal CCD
spectrometers comprised of a closed optics bench mounted in card slots of a PCB (printed circuit board) in the computer 20. Examples of the internal CCD spectrometers include the PC Plug-In Fiber Optic Miniature Spectrometer manufactured by Ocean Optics, and the Spectrophotometer manufactured by Hewlett Packard.
As shown in Figure 11, each of seven vessels 60 has a fiber optic UV probe 70 and dissolution paddle (not shown) disposed therein. Typically, one of the vessels 60 will contain the dissolution medium alone, or a placebo formulation in the dissolution medium, in order to provide a baseline spectra (e.g., to be used for a baseline correction calculation). The remaining six vessels 60 can hold the samples to be tested. Naturally, the system can also be configured with more or fewer than seven vessels. A light source 100, for example an LS-1 Deuterium light source as described above, is coupled to each of the fiber optic UV probes 70.
Each W probe 70 extends from the light source 100, into the vessel 60, and is coupled at its other end to a respective CCD spectrometer S0. Preferably, the internal core of the fiber consists of fused silica, which allows UV radiation to be efficiently propagated.
Figure 32 shows a first embodiment of the fiber optic W probe 70 having a shaft 101, at the remote end of which (not shown) is connected a light source 100 and a CCD
spectrometer 50.
Shaft 101 contains a pair of fibers (each preferably comprised of fused silica). At the proximal end of shaft 101, probe 70 has a detecting end 103 that contains a lens for focusing light that travels through the fibers. Detecting end 103, while being cylindrically-shaped in this embodiment, can have any suitable shape, so long as it does not interfere with the dissolution being detected. As shown in Figure 32, a flow cell 105 is formed as a bore, opening, aperture, or WO 01/16582 CA 02383906 2002-02-27 pCT/US00/23800 window through end 103. Dissolution medium flows freely through the flow cell 105, such that the dissolution within the medium can be measured.
UV radiation is transmitted from the source lamp through a first one of the fibers (which extends through shaft 101 into the probe) and through a quartz lens seated directly above the flow cell 105. UV radiation travels through flow cells 105 and is reflected off a mirror positioned at the terminal end of the probe on surface 109. The radiation is then directed back through the flow cell 105 and quartz lens into a second one of the fibers where it travels through shaft 101 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. As explained above, radiation returns from the fiber optic probe to the CCD
spectrometer where it is analyzed and quantitated. 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, preferably 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 system of Figure 11 may utilize open (i.e., uncovered) vessels or, most preferably, may utilize a "closed" (i.e., covered) vessel design as shown in Figure 12. An example of a suitable closed vessel is a Distek 5100 bathless unit. The major advantage of this closed design is to minimize loss of dissolution media.
In one embodiment of the system of Figure 11, probes 70 are inserted into vessels 60 for measurement of dissolution, and are held approximately midway between the surface of the dissolution medium and the bottom of the vessels 60. However, in certain applications (such as immediate release tablets), the presence of probes 70 within the medium may interfere with proper dissolution of the dosage into the medium, and readings taken by probes 70 that have been situated within vessels 60 may not accurately reflect the true dissolution rates. However, the USP currently requires that the dissolution medium be sampled approximately midway WO 01/16582 CA 02383906 2002-02-27 pCT/US00lZ3800 between the surface of the dissolution medium and the bottom of the vessels.
Accordingly, system 1, as shown in Figure 11, may alternatively use a dipping manifold to move the dip probes between a first position just below the surface of the dissolution medium and a second position midway between the surface of the dissolution medium and the bottom of the vessel. In this embodiment, the dipping manifold can be controlled to automatically dip the probes 70 into the second position only immediately or a short time period before readings are to be taken (e.g., every 1, 2, 5, or 10 minutes), and then to raise the probes into the first position when readings are not being taken. Alternatively, the dipping manifold can be controlled so as to selectively dip probes 70 into the vessels 60 between the first and second positions (or at any other position relative to the vessel). In this manner, should the operator of system 1 suspect that there is a turbidity problem, probes 70 can selectively be dipped into the medium (or raised within the medium) to a point outside the zone of disturbance caused by the agitation of the paddles within the medium. An example of a suitable dipping manifold is the manifold in the VanKel 7010 Dissolution Test Station. However, any other motorized mechanism suitable for moving the dip 1 S probes between the first and second positions can alternatively be used.
In the first embodiment of probe 70, as shown in Figure 32, the tip 111 of detecting end 103 of probe 70 is flat and the shaft 101 and detecting end 103 have the same diameter. A
potential problem associated with in situ probes is that bubbles may be formed when the probe is inserted into vessel 60. If these bubbles enter the flow cell, they may cause faulty spectral readings, and the resulting measurements may not be accurate. Therefore, in a second embodiment of probe 70, illustrated in Figure 33, the tip 112 of detecting end 103 of probe 70 is comically shaped. The pointed (or conical) tip 112 of probe 70 is intended to reduce the occurrence of bubbles within the fluid when probe 70 is first inserted into the fluid in vessel 60 for measuring the dissolution. In a third embodiment of probe 70, also illustrated in Figure 33, shaft 101 has a smaller diameter than detecting end 103 in order to reduce the profile of the probe 70 and reduce the hydrodynamic interference generated by the probe in the dissolution media.
In a fourth embodiment of probe 70, illustrated in Figure 34, detecting end 203 of probe 70 has a flow cell 205, bounded by upper surface 207 and lower surface 209, and the opposing ends of detecting end 203 are joined by a single arm 204, which is situated on the side of detecting end 203. This single arm construction is intended to enhance the flow through flow cell 205 and prevent particles from being caught within flow cell 205.
It should be noted that although in Figures 33 and 34, the tip 112 of detecting end 203 of probe 70 is comically shaped or pointed (as in the second embodiment described above) and the shaft 101 has a reduced profile (as in the third embodiment), the probe in accordance with the third embodiment may alternatively have a flat detecting end 103 and a uniform profile (as in the first embodiment). 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.
Figure 12 shows a vessel 60 with a dissolution paddle 90 disposed therein. The design of such a probe has the advantage of not causing flow aberration, since an additional probe need not be submerged in the dissolution media. Figure 13 shows the dissolution paddle 90 of this embodiment in greater detail. Fiber optic UV probe 70 is shown disposed within the hollow shaft of the dissolution paddle 90. In addition, a temperature sensor may optionally be disposed within the shaft of the paddle. Alternatively, the temperature sensor can be disposed elsewhere within the vessel 60, or eliminated altogether (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 Figure 12, a window 110 is provided on the shaft in order to allow the dissolution medium to flow through the shaft, thereby providing optical connectivity between the probe and the dissolution medium. A stirring motor 120 is also provided for rotation of the dissolution paddle 90. The stirring motor may be controlled via the computer or in any other known manner.
In a simple embodiment, the motor simply can be controlled by a switch.
As described above, the dissolution vessel temperature in the in-situ system can be controlled by a water bath in which vessels are submerged in order to maintain appropriate temperature. Alternatively, as shown in Figure 12, the dissolution vessel temperature in the in-situ system can be controlled by a bathless configuration, in which each vessel is surrounded by a heating element. This configuration reduces the size of the equipment and consequently the bench space and minimizes maintenance. It also allows temperature control of each vessel WO 01/16582 PCT/US00l23800 individually and also helps to minimize vibration associated with thermocirculation. A heating element appropriate for the bathless configuration is commercially available from Distek, Inc.
In an alternate design to the above-described general embodiments, probes 70 can be situated outside the dissolution vessels 60. In such an embodiment, near IR
that has limited interference from the container, such as glass vessel, is good candidate for use with such a detection probe. This embodiment avoids the issues of turbulence of the medium potentially interfering with measurements or the presence of the probes 70 within the medium potentially interfering with the dissolution of the medium.
The present invention can be practiced by detection systems other than those described above. For example, other fiber optic systems can be used, such as (1) Fluorescence, as described in the publication by Glazier, S.A. et al., Analytical Letters (1995) 28, 2607-24, (2) Infrared techniques, as described by Krska, R. et al. in Appl. Phys. Lett.
(1993) 63, 1868-70, (3) Near IR and Raman techniques, as described by Cram, D.J. and Hammond, G.S., Organic Chemistry, McCrraw-Hill (1959), all of which are hereby incorporated by reference, either with a grating or interferometer system. Each of these is a potentially powerful technique useful for dissolution testing. The techniques can be used with fiber optic spectrometers similar to that of UV, and these technologies are incorporated into the in-situ system similar to that for UV
detection.
In addition, an electrochemical detection system, such as quantitative electrochemical techniques as described by Cooper, J.C. and Hall, E.A., 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 can be used in the in-situ system with different electrode designs, such as platinum or glassy carbon electrodes, for evaluation of different products.
Furthermore, 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 WO 01/16582 PCT/USOOlZ3800 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 can be used the in-situ system as described herein.
Moreover, a non-fiber optic light source within probe 70 may be used as well.
In such an embodiment, as shown in Figure 35, the light is generated by an array of light emitting diodes (LEDs) 310 situated at the top 307 of flow cell 305. A number of LEDs (e.g, between 2 and 10), each with a different peak wavelength, are preferably placed at the top 307 of flow cell 305. A
conventional (e.g., silicon) photodiode would be situated at the bottom 309 of flow cell 305 in order to detect the amount of light that passes through the flow cell. A
"scan" is then acquired by illuminating the medium within the flow cell 305 with each diode in sequence.
The only connection from probe 70 is an electrical cable 313, which contains power, data and control wires. In addition, different types of detectors may also be used, such as lead sulfide, gallium arsenic (GaAs), gallium (Ga) and indium antimony (InSb).
Use of LEDs as a light source may be applied for dissolution testing, reaction monitoring, general laboratory solution analysis, turbidity measurements and pipeline analysis. Currently, LEDs are available in the NIR, UV, and visible regions. In general, the use of LEDs as a light source is appropriate in applications in which the spectroscopic investigation is required only for a limited number of wavelengths, such as quality control dissolution testing for a pharmaceutical dosage form. In this regard, the number of wavelengths which can be used in an LED light source is limited to the number of LEDs which can be housed in the detectors.
Another feature of the present invention is a servo system for achieving a constant energy level on all spectrometers used in dissolution testing. Generally, the servo function acquires WO 01/16582 CA 02383906 2002-02-27 pCT/US00/23800 reference spectra at varying integration times in order to achieve a given energy level. Longer integration times will produce a larger signal.
As shown in Figure 36, the servo is controlled by a control module, which acquires reference spectra at varying integration times in order to achieve a given energy level. First, the servo acquires a reference scan at a lowest predetermined integration time.
The servo then acquires a second reference scan with a new integration time. This procedure is repeated iteratively until an integration time is chosen that produces the desired level of energy, called the Target Percent Relative Energy.
In order to perform these extrapolations accurately, the servo assumes that the spectrometer's intensity response is relatively linear over short integration time intervals and that the intensity response is monotonically increasing over the range from the lowest predetermined integration time (e.g., 3.6 ms) to a largest predetermined integration time (e.g. 6,534.7 ms). As set forth below, if these assumptions are not valid for a particular spectrometer, then that spectrometer is considered to be non-functional and an error message is generated.
In the following discussion, the servo function will be explained in connection with a system in which the lowest predetermined integration time is 3.6 ms (which is the minimum integration time of a Zeiss spectrometer) and 6,534.76 ms (which is the maximum integration time of the Zeiss spectrometer).
Two parameters are associated with the servo function, namely the Target Percent Relative Energy and the Target Precision. The default values for these parameters are 80% and 0.1%, respectively. However, other values may alternatively be used. The servo starts with an Integration Time of 3.6 ms (the lowest predetermined integration time), by acquiring a data point using this value and obtaining the relative energy from the spectrometer. The Servo will then perform a linear extrapolation using the measured relative energy from the last data step in order to determine what the new integration time should be in order to obtain the target relative energy.
The servo computes the new integration time for each subsequent data step using the formula ITN = IT * (TRE/MRE), where:
WO ~l/16$82 CA 02383906 2002-02-27 pCl,/[JS~~n380~
ITN is the New Integration Time;
IT is the Integration Time;
THE is the Target Relative Energy (percent); and MRE is the Measured Relative Energy (percent).
The servo function terminates whenever MRE is within Target Precision units from the Target Percent Relative Energy. The servo calculates a Low Limit (Target Percent Relative Energy - Target Precision) and a High Limit (Target Percent Relative Energy +
Target Precision). The servo then terminates at the point that the Measured Relative Energy is greater than or equal to the Low Limit and Measured Relative Energy is less than or equal to the High Limit.
For example, using the starting values of a Target Relative Energy of 80% and a Target Precision of 0.1%, if an integration time of 3.6 ms resulted in a measured relative energy of 2%, then the integration time would need to be increased by approximately 40 times (i.e., the ratio of Target Relative Energy to Measured Relative Energy, or 80% / 2%). Accordingly, the calculated new integration time is 144 ms (i.e., 40 times 3.6 ms). Assuming that the spectrometer is perfectly linear, this result provides a measured relative energy of 80% for an integration time of 144 ms, meaning that the servo could terminate its loop after just two steps.
However, this is seldom the case, as illustrated by the following table. In step 2, the integration time of 144 ms derived above results in a measured relative energy of 90%. The ratio of THE to MRE of 0.89 indicates that the integration time needs to be decreased from 144 ms to 128 ms. Then, as shown in step 3, the integration time of 128 ms results in a reduced measured relative energy of only 85%, and the resulting ratio of THE to MRE of 0.94 provides a slightly smaller new integration time of 120.5 ms.
In step 4, the integration time of 120.5 results in a further relative energy of 81%, which is still slightly outside the desired limits of 80% ~ 0.1 %. The resulting ratio of THE to MRE of 0.99 provides a new integration time of 119Ø In this example, an integration time of 119.0 ms results in precisely 80% relative energy, and the iterative process is terminated at step 5.
Table 4 Step IT MRE TRE/MRE ITN
Ratio 1 3.6 2 40.00 144.0 2 144.0 90 0.89 128.0 3 128.0 85 0.94 120.5 4 120.5 81 0.99 119.0 119.0 80 1.00 119.0 5 The data from the above reference scans for obtaining the Target Relative Energy set forth below in Table 4 are plotted in Figure 37. The plotted line in Figure 37 illustrates that the spectrometer used is slightly non-linear, but within acceptable limits.
As set forth above, the system preferably generates error messages when a spectrometer fails to perform within acceptable limits for the servo system. One indicator of a non-functioning spectrometer is a non-linear intensity response, which occurs when MRE/MREp _<
0.1 * ITN/IT.
The servo system assumes that the spectrometer intensity response is relatively linear such that the increases and/or decreases in relative energy are relatively proportional to the increase and/or decrease in the integration time, from one step to the next. A non-linear intensity response occurs when the proportional relative energy increase/decrease is less than one/tenth that of the integration time increase/decrease. If the intensity Response is non-linear, the spectrometer is considered to be non-functional and an error message is generated. Another instance of a non-functioning spectrometer is caused by the use of an extremely high light intensity, which occurs whenever MRE = 100 and IT = MinIntegrationTime, i.e., the relative energy is equal to 100%
and the integration time is equal to the minimum integration time. In addition, a non-functioning spectrometer can also be caused by a high light intensity, which occurs whenever MRE >
HighLimit and IT = MinIntegrationTime, i.e., the relative energy is greater than the desired HighLimit and the integration time is equal to the minimum integration time.
Similarly, a non-functioning spectrometer may be caused by the use of low light intensity, which occurs whenever MRE < LowLimit and IT > MaxIntegrationTime, i.e., the relative energy is less than the desired LowLimit and the integration time is equal to the maximum integration time. If any of these conditions is detected, a respective error message is generated. In response, the user will investigate the light intensity, and, if appropriate, lower (or increase) the light intensity to an acceptable level. In addition, if the servo function performs more than a predetermined maximum number of iterations (e.g. 100) without reaching the Target Relative Engery (+/-Target Precision), an error message will be generated.
Spectral Analysis Method With Scattering Compensation As set forth above, in accordance with an embodiment of the present invention, the data received from each probe is analyzed to determine the percentage of active agent dissolved over time. While this embodiment of the invention will be discussed with reference to the system of Figure 11, other in situ dissolution systems described herein may alternatively be employed.
One of the major obstacles in the development of analytical systems with in-situ dissolution monitoring techniques is that the in situ nature of the method excludes any sample pretreatment. A standard practice in spectroscopic analysis is to filter the sample solution prior to any optical analysis. The reason for this is simple: any particulate suspended in the sample can cause scattering that may interfere with the spectroscopic analysis of the compound under study. However, since an in situ dissolution technique inherently forbids this sort of sample pretreatment, an alternative approach is needed.
The simplest approach would to utilize a single point baseline correction where the absorbance of a single point is subtracted from the absorbance of the analytical measurement.
This works well if the scattering level is small in comparison to the level of the analytical absorption (as in the case of tramadol). However, in situations where the scattering response is the dominant spectra, a different approach is needed.
Tangential Peak Area Spectral Analysis Method In view of the scattering problems set forth above, a mathematical method is needed that selectively analyzes only the region of the spectrum that results from the absorption of the analyte. One method that accomplishes this goal is the "floating triangle"
method, which was used to quantitate the amount of hydromorphone HCl in thel2 mg capsules of Example 5 set forth above The mathematical basis of this quantitation method is illustrated in Figure 14.
Since the height h of the triangle is independent of the slope and level of the baseline b, this measurement can be directly related to the amount of hydromorphone HCl in solution.
Although this method does provide adequate selectivity towards hydromorphone, an improved quantitation method that is less susceptible to scattering interference is desirable.
In accordance with a tangential peak area method in accordance with the present invention, the area of a right triangle is subtracted from the total area under the curve of a relevant spectral region. The area of the right triangle, which is described in more detail below, closely approximates the remaining scattering contribution. Figure 15 shows how the area under the curve is first defined by the spectral range of analyte (260-296 nm for hydromorphone HCl).
A baseline subtraction of the curve is then applied. The area of the baseline-subtracted region is then determined by a trapezoidal approximation (from the Trapezoidal Rule, see Stewart, James, Calculus, 2°d edition 1991, pp.455).
The measured peak area (MPA), which is free from scattering interference, is then determined by subtracting the area of the right triangle from the total area under the curve, wherein the right triangle is defined by the following points baseline (i), f(i), and baseline (ii), and the base of the triangle is defined by the baseline(i to ii), as shown in Figure 16. In Figure 16, f(x) intersects the baseline at the higher end (point ii) of the spectral region. As one of ordinary skill in the art will appreciate, however, this is merely illustrative, and it is possible that other spectrums may have a baseline value which intersect f(x) at the lower end (i) of the spectral region. The MPA is proportional to the amount of drug substance in solution.
The MPA can be calculated in the following manner. As the calculations are relatively simple, they are particularly well suited for real-time data generation:
The baseline measurement is first subtracted from every point in the spectral region (baseline corrected).
2. The Area Under the Curve (AUC) is then calculated using the Trapezoidal Rule, which divides up the area under the curve into trapezoids and then calculates the area of the trapezoids. The AUC is then defined as the sum of areas of the individual trapezoids. The area of each trapezoid is defined by the equation A, = 0x (y'-' 2 y' ~ , where A; is the area of the i'~
interval (trapezoid), and y;_1 and y; are the absorbance values for the given and the previous interval. Therefore, the area under the curve (AUC) is given by the equation (y1-1 + y!
A.U.C.='~ ~X
Figure 15 shows this area under the curve as the striped region. This area is not corrected for scattering and is not used directly for analytical measurements in this embodiment. In order to correct for scattering, the portion of the area that contains the scattering interference must be removed. This is accomplished by subtracting everything but the analytical "hump" that results from the absorption of our analyte. This can be very closely approximated by removing the area of the right triangle, as shown in Figure 16. The area of the right triangle (ART) is defined by the equation ART = ~ 2~y , which is one half the base times the height, where the base 1 S 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 are determined, the measured peak area (MPA) is defined as the difference of the two:
Measured Peak Area = AUC - ART. This measurement can then be used to generate analytical data.
Example 6 In order to demonstrate how the tangential peak area method more accurately calculates the amount of analyte dissolved, dissolution tests were conducted on 12 mg., 16 mg, 24 mg, and 32 mg hydromorphone capsules. The capsules have the following ingredients:
Dosage and Weight Ingredients Weight Ratio (%) CAPSULES EUDRAGIT RSPO 63.75 Total Wt. Stearyl alcohol 22.50 120 mg. Ethocel Standard 7 3.75 Premium CAPSULES EUDRAGIT RSPO 63.75 Total Wt. Stearyl alcohol 22.50 160 mg. Ethocel Standard 7 3.75 Premium CAPSULES EUDRAGIT RSPO 63.75 Total Wt. Stearyl alcohol 22.50 240 mg. Ethocel Standard 7 3.75 Premium CAPSULES EUDRAGIT RSPO 63.75 Total Wt. Stearyl alcohol 22.50 320 mg. Ethocel Standard 7 3.75 Premium Dissolution data was obtained using the HPLC method at 1 hour, 2 hours, 12 hours, 18 hours, and 24 hours, in situ using the floating triangle method (shown in Figure 14) sampling every 10 minutes, and in situ using the tangential peak area method (shown in Figure 15) sampling every 10 minutes.
The HPLC data was generated as follows. Dissolution was carried out using USP
Apparatus 1 Basket Method <711> at 100 RPM. The dissolution media was 900 ml of simulated intestinal fluid without enzymes plus 3 grams sodium chloride per liter at 37° C. The samples used were 12 mg, 24 mg and 32 mg capsules of controlled release hydromorphone as described above. The samples were withdrawn at 1 hour, 2 hours, 12 hours, 18 hours and 24 hours and analyzed by HPLC (High Pressure Liquid Chromatography) for hydromorphone HCI.
The samples were then separated on a reverse phase C,8 Waters Nova-Pak column at 30° C, using a mobile phase at pH of 2.9 consisting of sodium dodecyl sulfate, acetonitrile, sodium phosphate monobasic, and water. UV absorbance detection at 280 nm was used for quantitative determination.
The data for the in situ dissolution was generated using the dissolution apparatus of Figure 11, using USP Apparatus 2 Paddle Method at 100 RPM. The dissolution media was 500 ml of simulated intestinal fluid (without enzyme) maintained at 37° C
with 3 grams of sodium chloride per liter. The samples used were 12 mg, 24 mg and 32 mg capsules of controlled release hydromorphone as described above. The dissolution rated was continuously monitored by a UV
Fiber Optic absorbance dip probe, with a 20 mm path length and manufactured by Ocean Optics.
The dip probe was placed in the dissolution vessel, adjacent to the mixing shaft as shown in Figure 11. The deuterium light source was manufactured by Oriel Instruments, and the spectrometer was an Ocean Optics PC1000 Fiber Optic CCD Spectrometer. An absorbance spectrum of the dissolution media was generated every 10 minutes for a period of 24 hours.
The measured spectrums were then processed in accordance with the floating triangle method of Figure 14, and the tangential peak area method of Figures 15 and 16.
The results of these tests are shown in Figures 17 through 20, which demonstrate that the tangential peak area method in accordance with the invention provides results that are equal to or superior to those generated with the floating triangle method.
The most dramatic increase in accuracy is seen for the l2mg sample (Figure 17), where the improved floating triangle method corresponds quite nicely with the HPLC
data. This is probably due to the use of a greater number of wavelengths in the Tangential Peak Area Method (TPAM)(19 points: 260, 262, ... 296 nm) as compared to the floating triangle method (3 points:
260, 280, 310), which increase sensitivity and selectivity. This benefit is most evident at the 12 mg capsule because the 12 mg capsule has the smallest amount of hydromorphone and, therefore, is more susceptible to inaccuracies flowing from scattering affects.
The underlying data for the graphs of Figures 17 through 19 are set forth below in Tables 5 through 8:
Table 5: HHCR 12 mg Time Floatin Trian 1e TPAM 12m HPLC
Method 0.0 0.00% 0.01%
hr 0.2 0.28% 5.36%
hr 0.3 8.76% 9.04%
hr 0.5 9.91% 10.91%
hr 0.7 11.11 % 11.68%
hr 0.8 12.43% 13.21 hr 1.0 13.99% 14.48% 8.80%
hr 1.2 15.20% 15.79%
hr Time Floatin Trian 1e TPAM 12m HPLC
Method 1.3 16.49% 17.23%
hr 1.5 17.87% 18.35%
hr 1.7 18.91% 19.96%
hr 1.8 2 21.11%
hr 0.31%
2.0 ____ 22.58% 16.43%
hr _ 21.32%
2.2 23.00% 3.32%
hr 2 2.3 23.93% _ hr _ 25.00%
2.5 - -25.16% - 26-.09%
hr 2.7 26.02% 27.63%
hr 2.8 26.89% 28.47%
hr 3.0 28.11 % 29.31 hr 3.2 29.07% 30.36%
hr 3.3 30.36% 31.07%
hr 3.5 31.20% 32.83%
hr 3.7 32.26% 33.35%
hr 3.8 33.29% 34.63%
hr 4.0 34.43% 35.79%
hr 4.2 35.37% 36.68%
hr 4.3 36.52% 37.62%
hr 4.5 37.11 % . 39.04%
hr 4.7 38.45% 40.01 hr 4.8 40.00% 40.78%
hr 5.0 41.18% 42.34%
hr 5.2 42.04% 43.42%
hr 5.3 42.75% 44.70%
hr 5.5 43.43% 45.38%
hr 5.7 44.28% 46.17%
hr 5.8 45.31 % 46.96%
hr 6.0 46.18% 48.00%
hr 6.2 46.98% 49.28%
hr 6.3 48.22% 49.99%
hr 6.5 49.14% 50.92%
hr 6.7 50.21 % 51.52%
hr 6.8 50.91 % . 52.81 hr 7.0 51.90% 53.54%
hr 7.2 52.77% 54.44%
hr 7.3 53.65% 55.47%
hr 7.5 54.84% 56.49%
hr 7.7 55.63% 57.85%
hr 7.8 56.80% 58.14%
hr 8.0 57.66% 59.32%
hr 8.2 58.72% 60.18%
hr 8.3 59.77% 61.41 hr 8.5 60.20% 62.73%
hr 8.7 60.73% 63.12%
hr 8.8 61.57% 63.66%
hr 9.0 62.06% 64.61 hr 9.2 63.22% 65.04%
hr Time Floatin Trian 1e TPAM 12m HPLC
Method 9.3 63.78% 66.53%
hr 9.5 64.70% 67.34%
hr.
9.7 65.56% 68.01 hr 9.8 66.42% 68.85%
hr 10.0 66.70% 69.59%
hr 10.2 67.10% 69.78%
hr 10.3 67.46% 70.05%
hr 10.5 68.05% 70.87%
hr 10.7 68.73% 71.75%
hr 10.8 69.46% 72.29%
hr 11.0 70.47% 72.77%
hr 11.2 71.47% 74.08%
hr 11.3 72.25% 74.46%
hr 11.5 73.04% 75.15%
hr 11.7 73.66% 76.47%
hr 11.8 74.74% 77.01 hr 12.0 75.10% 77.85% 77.77%
hr 12.2 74.86% 78.62%
hr 12.3 75.16% 78.25%
hr 12.5 75.28% 78.30%
hr 12.7 75.83% 78.84%
hr 12.8 76.16% 79.42%
hr 13.0 77.09% 79.66%
hr 13.2 77.73% 80.74%
hr 13.3 78.77% 81.32%
hr 13.5 79.80% 82.12%
hr 13.7 79.98% 83.24%
hr 13.8 81.03% 83.63%
hr 14.0 81.44% 84.39%
hr 14.2 81.49% 85.19%
hr 14.3 82.12% 85.16%
hr 14.5 82.37% 85.87%
hr 14.7 82.95% 86.31 hr 14.8 83.53% 86.72%
hr 15.0 83.92% 87.25%
hr 15.2 84.15% 87.61 hr 15.3 84.71 % 87.92%
hr 15.5 85.11 % 88.62%
hr 15.7 85.29% 88.68%
hr 15.8 86.04% 88.97%
hr 16.0 85.93% 89.55%
hr 16.2 86.26% 89.68%
hr 16.3 87.13% 90.12%
hr 16.5 87.02% 90.96%
hr 16.7 87.42% 90.71 hr 16.8 87.78% 91.26%
hr 17.0 88.15% 91.40%
hr 17.2 88.29% 91.84%
hr Time Floatin Trian TPAM 12m HPLC
1e Method 17.3 88.93% 91.94%
hr 17.5 89.02% 92.53%
hr 17.7 89.26% 92.76%
hr 17.8 89.79% 92.96%
hr 18.0 89.73% 93.60%
hr 18.2 90.09% 93.51 hr 18.3 90.36% 93.95%
hr 18.5 90.61 % 94.39% 95.15%
hr 18.7 90.47% 94.37%
hr 18.8 90.91 % 94.45%
hr 19.0 90.89% 94.56%
hr 19.2 91.00% 94.55%
hr 19.3 91.13% 95.18%
hr 19.5 91.46% 95.32%
hr 19.7 91.43% 95.95%
hr 19.8 91.62% 95.42%
hr 20.0 92.06% 95.93%
hr 20.2 92.38% 96.12%
hr 20.3 92.63% 96.48%
hr 20.5 92.95% 96.55%
hr 20.7 93.22% 97.16%
hr 20.8 93.00% 97.14%
hr 21.0 93.23% 97.29%
hr 21.2 93.09% 97.75%
hr 21.3 93.41 % 97.43%
hr 21.5 93.51 % 97.31 hr 21.7 93.81 % 98.09%
hr 21.8 93.98% 98.26%
hr 22.0 94.25% 98.50%
hr 22.2 94.43% 98.47%
hr 22.3 94.27% 98.45%
hr 22.5 94.37% 98.40%
hr 22.7 94.82% 99.18%
hr 22.8 95.08% 99.16%
hr 23.0 94.80% 98.85%
hr 23.2 95.36% 98.95%
hr 23.3 95.09% 99.51 hr 23.5 95.55% 99.55%
hr 23.7 95.72% 99.64%
hr 23.8 96.06% 99.97%
hr 24.0 100.05% 100.07%
hr Table 6: HHCR 24 mg Time Floatin Trian 1e TPAM 24m HPLC
24 m 0.0 0.27% 0.10%
hr 0.2 6.31 % 7.58%
hr Time- Floatin Trian 1e TPAM 24m HPLC
24 m 0.3 8.38% 9.98%
hr 0.5 10.11 % 11.83%
hr 0.7 11.82% 13.56%
hr 0.8 13.13% 14.85%
hr 1.0 14.54% 16.22% 13.14%
hr 1.2 15.85% 17.41 hr 1.3 17.37% 18.93%
hr 1.5 18.59% 20.30%
hr 1.7 19.88% 21.59%
hr 1.8 21.16% 22.84%
hr 2.0 22.45% 24.04% 19.85%
hr 2.2 23.78% 25.66%
hr 2.3 24.94% 26.85%
hr 2.5 26.39% 28.23%
hr 2.7 27.57% 29.37%
hr 2.8 28.79% 30.70%
hr 3.0 29.99% 32.16%
hr 3.2 31.33% 33.43%
hr 3.3 32.58% 34.60%
hr 3.5 33.89% 36.06%
hr 3.7 35.11 % 37.22%
hr 3.8 36.59% 38.68%
hr 4.0 37.51 % 39.78%
hr 4.2 39.01 % 41.28%
hr 4.3 40.20% 42.29%
hr 4.5 41.43% 43.64%
hr 4.7 42.62% 45.10%
hr 4.8 44.07% 46.21 hr 5.0 45.28% 47.49%
hr 5.2 46.62% 48.85%
hr 5.3 47.70% 49.94%
hr 5.5 49.18% 51.49%
hr 5.7 50.27% 52.62%
hr 5.8 51.34% 53.49%
hr 6.0 52.50% 54.72%
hr 6.2 53.73% 56.04%
hr 6.3 54.92% 57.24%
hr 6.5 56.01 % 58.32%
hr 6.7 57.10% 59.48%
hr 6.8 58.24% 60.61 hr 7.0 59.27% 61.74%
hr 7.2 60.41 % 62.88%
hr 7.3 61.53% 64.02%
hr 7.5 62.63% 65.10%
hr 7.7 63.56% 66.04%
hr 7.8 64.54% 67.21 hr 8.0 65.51 % 68.08%
hr 8.2 66.76% 69.11 hr WO 01/16582 PCT/US00l23800 Time Floatin Trian 1e TPAM 24m HPLC
- 24 m 8.3 67.65% 70.31 hr 8.5 68.73% 71.31 hr 8.7 69.71 % 72.48%
hr 8.8 70.54% 73.08%
hr 9.0 71.42% 73.89%
hr 9.2 72.36% 75.01 hr 9.3 73.51 % 76.03%
hr 9.5 74.25% 76.78%
hr 9.7 75.02% 77.84%
hr 9.8 75.74% 78.35%
hr 10.0 76.67% 79.28%
hr 10.2 77.33% 80.13%
hr 10.3 78.17% 80.93%
hr 10.5 78.74% 81.54%
hr 10.7 79.49% 82.37%
hr 10.8 80.32% 83.29%
hr 11.0 80.74% 83.49%
hr 11.2 81.75% 84.55%
hr 11.3 82.25% 85.07%
hr 11.5 83.16% 85.92%
hr 11.7 83.62% 86.38%
hr 11.8 84.28% 87.04%
hr 12.0 84.87% 87.74% 84.15%
hr _ _ 88.21 % -12.2 85.35%
hr _ 12.3 - - 85.98% 88.82% -hr 12.5 86.44% 89.29%
hr 12.7 86.92% 89.75%
hr 12.8 87.28% 90.13%
hr 13.0 87.94% 91.00%
hr 13.2 88.29% 91.21 hr 13.3 88.84% 91.62%
hr 13.5hr 89.40% 92.14%
13.7 - - $9.81 % 92.60%
hr-13.8 - - 9.42% 93.01 hr 14.0 90.97% 93.60%
hr 14.2 91.34% 94.02%
hr 14.3 91.47% 94.23%
hr 14.5 91.96% 94.72%
hr 14.7 92.41 % 95.03%
hr 14.8 92.95% 95.62%
hr 15.0 93.04% 95.76%
hr 15.2 93.64% 96.34%
hr 15.3 93.85% 96.57%
hr 15.5 94.05% 96.79%
hr 15.7 94.43% 97.07%
hr 15.8 94.77% 97.31 hr 16.0 95.08% 97.59%
hr 16.2 95.59% 98.03%
hr Time Floatin Trian TPAM 24m HPLC
1e 24 m 16.3 95.47% 98.12%
hr 16.5 95.84% 98.55%
hr 16.7 96.13% 98.71 hr 16.8 96.24% 98.98%
hr 17.0 96.36% 99.09%
hr 17.2 96.75% 99.42%
hr 17.3 96.92% 99.62%
hr 17.5 97.33% 100.14%
hr 17.7 97.43% 100.27%
hr 17.8 97.61 % 100.26%
hr 18.0 97.74% 100.37%
hr 18.2 97.98% 100.68%
hr 18.3 98.32% 101.17%
hr 18.5 98.43% 101.22% 98.09%
hr 18.7 98.46% 101.20%
hr 18.8 98.59% 101.44%
hr 19.0 98.54% 101.29%
hr 19.2 98.87% 101.77%
hr 19.3 99.24% 101.77%
hr 19.5 99.37% 102.07%
hr 19.7 99.47% 102.26%
hr 19.8 99.68% 102.34%
hr 20.0 99.75% 102.53%
hr 20.2 99.86% 102.50%
hr 20.3 99.65% 102.53%
hr 20.5 100.08% 102.66%
hr 20.7 '100.13% 103.08%
hr 20.8 100.20% 103.00%
hr 21.0 100.27% 103.17%
hr 21.2 100.61 % 103.43%
hr 21.3 100.58% 103.64%
hr 21.5 100.70% 103.42%
hr 21.7 100.80% 103.55%
hr 21.8 100.75% 103.61 hr 22.0 101.08% 103.81 hr 22.2 100.84% 103.74%
hr 22.3 101.23% 104.04%
hr 22.5 101.22% 104.21 hr 22.7 101.43% 104.07%
hr 22.8 101.54% 104.34%
hr 23.0 101.72% 104.57%
hr 23.2 101.50% 104.47%
hr 23.3 101.76% 104.69%
hr 23.5 101.93% 104.63%
hr 23.7 101.74% 104.46%
hr 23.8 101.98% 104.84%
hr 24.0 102.08% 104.94% 101.67%
hr ~
WO 01/16582 PCT/ITS00l23800 Table 7: HHCR 16 mg Time Floatin Trian TPAM 16m HPLC
1e Method 0.0 0.34% -0.03%
hr 0.2 5.76% 6.96%
hr 0.3 7.50% 8.60%
hr 0.5 8.59% 10.10%
hr 0.7 9.72% 11.24%
hr 0.8 10.97% 12.19%
hr 1.0 12.14% 13.54% 10.27/
hr 1.2 13.38% 14.82%
hr 1.3 14.71 % 16.00%
hr 1.5 15.39% 16.84%
hr 1.7 16.81 % 18.12%
hr 1.8 17.99% 19.15%
hr 2.0 18.94% 20.15% 17.97/
hr 2.2 19.95% 21.12%
hr 2.3 21.20% 22.41 hr 2.5 22.15% 23.40%
hr 2.7 23.32% 24.36%
hr 2.8 24.47% 25.56%
hr 3.0 25.55% 26.76%
hr 3.2 26.81 % 27.83%
hr 3.3 27.71 % 28.56%
hr 3.5 28.78% 29.90%
hr 3.7 29.81 % 30.80%
hr 3.8 30.82% 31.92%
hr 4.0 31.86% 32.80% 30.99%
hr 4.2 32.76% 33.50%
hr 4.3 33.86% 34.70%
hr 4.5 34.77% 35.76%
hr 4.7 35.89% 36.84%
hr 4.8 36.56% 37.32%
hr 5.0 37.66% 38.63%
hr 5.2 38.49% 39.62%
hr 5.3 39.28% 40.30%
hr 5.5 40.20% 41.21 hr 5.7 41.43% 42.27%
hr 5.8 41.99% 43.06%
hr 6.0 43.13% 43.89%
hr 6.2 43.95% 44.68%
hr 6.3 44.84% 45.65%
hr 6.5 45.80% 46.64%
hr 6.7 46.61 % 47.48%
hr 6.8 47.53% 48.43%
hr 7.0 48.01 % 48.94%
hr 7.2 49.11 % 49.80%
hr 7.3 49.78% 50.84%
hr 7.5 ~ 50.48% 51.30%
hr WO 01/16582 PCT/US00lZ3800 Time Floatin Trian TPAM 16m HPLC
1e Method 7.7 51.41 % 52.49%
hr 7.8 52.23% 52.93%
hr 8.0 52.88% 53.59%
hr 8.2 53.94% 54.56%
hr 8.3 54.41 % 55.30%
hr 8.5 55.28% 56.02%
hr 8.7 56.11 % 56.89%
hr 8.8 56.93% 57.69%
hr 9.0 57.39% 58.04%
hr 9.2 58.29% 59.08%
hr 9.3 58.92% 59.85%
hr 9.5 59.71 % 60.53%
hr 9.7 60.33% 61.16%
hr 9.8 60.92% 61.78%
hr 10.0 61.53% 62.61 hr 10.2 62.44% 63.23%
hr 10.3 63.01 % 63.87%
hr 10.5 63.81 % 64.51 hr 10.7 64.33% 64.92%
hr 10.8 65.16% 65.91 hr 11 65.28% 66.10%
.0 hr _ 66.35% 66.87%
_ 11.2 hr 11.3 67.01 % 67.86%
hr 11.5 67.40% 68.17%
hr 11.7 68.38% 69.05%
hr 11 68.64% 69.23%
.8 hr _ 69.18% 6g.98%
12.0 hr 12.2 70.12% 70.71 hr 12.3 70.42% 71.30%
hr 12 71.20% 71.86%
.5 hr _ 71.75% 72.57%
12.7 hr 12.8 ?2.29% 73.01 hr 13.0 72.80% 73.28%
hr 13.2 73.33% 74.02%
hr 13.3 73.78% 74.59%
hr 13.5 74.61 % 75.03%
hr 13.7 74.99% 75.87%
hr 13.8 75.43% 76.09%
hr 14.0 76.02% 76.74%
hr 14.2 76.63% 77.27%
hr _ 76.91 % 77.51 14.3 hr 1 77.60% 78.33% - -4.5 hr _ 77.76% 78.84%
14.7 hr 14.8 78.16% 78.99%
hr 15.0 78.79% 79.40% -hr- -15.2 __ 79.87%
hr 79.08%
15.3 79.79% 80.31 hr 15.5 80.10% 80.84%
hr ~5 Time Floatin Trian TPAM 16m HPLC
1e Method 15.7 80.72% 81.26%
hr 15.8 80.88% 81.63%
hr 16.0 81.30% 82.15% 84.33%
hr 16.2 81.61 % 82.33%
hr 16.3 82.06% 82.63%
hr 16.5 82.32% 82.93%
hr 16.7 82.94% 83.68%
hr 16.8 83.28% 83.70%
hr 17.0 83.65% 84.04%
hr 17.2 83.95% 84.65%
hr 17.3 84.27% 85.21 hr 17.5 84.89% 85.62%
hr 17.7 85.13% 86.04%
hr 17.8 85.55% 86.05%
hr 18.0 86.14% 86.79% 89.09%
hr 18.2 86.59% 87.22%
hr 18.3 86.88% 87.39%
hr 18.5 87.37% 87.83%
hr 18.7 87.64% 88.28%
hr 18.8 _ . ..88.07% . 88.93% .
hr .
19.0 88.71 % 89.38%
hr 19.2 88.99% 89.67%
hr 19.3 89.15% 89.96%
hr 19.5 89.27% 89.98%
hr 19.7 89.84% 90.60%
hr 19.8 90.13% 90.82%
hr 20.0 90.45% 91.47%
hr 20.2 ~ 90.70% 91.37%
hr 20.3 hr 20.5 91.59% 92.25%
hr 20.7 91.27% 92.13%
hr 20.8 91.53% 92.73%
hr 21.0 91.86% 92.59%
hr 21.2 92.18% 92.97/u hr 21.3 92.46% 93.35%
hr 21.5 92.66% 93.58%
hr 21.7 ' 92.78% 93.79%
hr 21.8 93.01 % 94.09%
hr 22.0 93.12% 94.10%
hr 22.2 93.49% 94.72%
hr 22.3 93.44% 94.78%
hr 22.5 93.36% 94.54%
hr 22.7 94.05% 95.08%
hr 22.8 94.09% g5.37%
hr 23.0 94.36% 95.34%
hr 23.2 94.57% 95.55%
hr 23.3 94.57% 95.65%
hr 23.5 94.77% 96.24%
hr yG
Time Floatin Trian 1e TPAM 16m HPLC
Method 23.7 95.04% 96.19%
hr 23.8 - 95.26% 96.69%
hr 24.0 95.08% 96.48% 97.67%
hr Table 8: HHCR 32 mg Time Floatin Trian 1e TPAM 32m HPLC
Method 0.0 0.36% 0.11 hr 0.2 6.08% 6.60%
hr 0.3 7.75% 8.64%
hr-0.5 9.00% 9.68%
hr 0.7 10.13% 10.86%
hr 0.8 11.29% 12.22%
hr 1.0 12.53% 13.42% 11.07%
hr 1.2 13.71 % 14.60%
hr 1.3 14.95% 15.84%
hr 1.5 16.07% 16.93%
hr 1.7 17.25% 18.23%
hr 1.8 18.33% 19.38%
hr 2.0 19.52% 20.49% 18.94%
hr 2.2 20.57% 21.60%
hr 2.3 21.73% 22.77%
hr 2.5 22.83% . .- 23.81%
hr ..
-2.7 24.04% 25.11 hr 2.8 24.98% 26.18%
hr 3.0 26.14% 27.03%
hr 3.2 27.16% 28.16%
hr 3.3 28.24% 29.29%
hr -3.5 29.22% 30.33%
h~--3.7 30.32% 31.33%
hr 3.8 31.21 % 32.29%
hr 4.0 32.39% 33.46% 31.34%
hr 4.2 33.13% 34.17%
hr 4.3 34.01 % 35.13%
hr 4.5 35.06% 36.05%
hr 4.7 36.03% 37.11 hr 4.8 37.02% 38.20%
hr 5.0 37.84% 39.14%
hr 5.2 38.82% 39.86% -.
hr 5.3 39.70% 40.86%
hr 5.5 40.61% 41.71%
hr 5.7 41.60% 42.59%
hr 5.8 42.35% 43.65%
hr 6.0 43.26% 44.43%
hr 6.2 44.05% 45.21 hr 6.3 44.94% 46.10%
hr 6.5 45.81 % 47.02%
hr WO 01/16582 PCT/US00lZ3800 Time Floatin Trian 1e TPAM 32m HPLC
Method 6.7 46.69% 48.04%
hr 6.8 47.55% 48.76%
hr 7.0 48.27% 49.63%
hr 7.2 49.23% 50.45%
hr 7.3 50.01% 51.21%
hr 7.5 50.66% 51.95%
hr 7.7 51.57% 52.75%
hr 7.8 52.41 % 53.66%
hr 8.0 53.05% 54.51 hr 8.2 53.76% 55.05%
hr 8.3 54. 56.03%
hr 74%
8.5 _ 56.52%
hr 55.38%
8.7 56.08% 57.39%
hr 8.8 56.95% 58.18%
hr 9.0 57.69% 58.84%
hr 9.2 58.38% 59.55%
hr 9.3 59.14% 60.47 hr %
9.5 59.71 % -. _ _ -hr - 60.78%
9.7 ..:. 6.49% - - 81.64% -hr 9.8 61.10% 62.49%
hr 10.0 61.7 63.23%
hr 6%
- 10.2 _ 8% -.
hr-- ..... 62.45% 83.8 10.3 -63.07% -. - _ hr x.58%
10.5 63.84% 65.47%
hr 10.7 64 65.99 hr .4 %
5%
_ _ _ 10.8 _ - 86.64%
hr -. --85.08%--.
11.0 65.64% 67.24%
hr 11.2 _ ... 66:49% 88.01 hr 11.3 66.95% 68.41 hr 11.5 67.55% 69.24%
hr 11.7 68.13% 69.74%
hr 11.8 68.83% 70.29%
hr 12.0 69.36% 71.07%
hr 12.2 70.04% 71.57%
hr 12.3 70.65% 72.26%
hr 12.5 71.24% 72.71 hr 12.7 71:73% 73.28%
hr 12.8 72.33% 73.95%
hr 13.0 72.91 % 74.43%
hr 13.2 73.38% 75.08%
hr 13.3 73.88% 75.65%
hr 13.5 .. .. 74:50% 76.07%
hr 13.7 75.12% 76.72%
hr 13.8 75.53% 77.25%
hr 14.0 76.05% 77.70%
hr 14.2 76.62% 78.23%
hr 14.3 77.18% 78.86%
hr 14.5 77.70% 79.45%
hr y~
Time Floatin Trian TPAM 32m HPLC
1e Method 14.7 78.17% 79.96%
hr 14.8 78.63% 80.56%
hr 15.0 79.01 % 80.82%
hr 15.2 79.48% 81.36%
hr 15.3 79.95% 81.75%
hr 15.5 80.59% 82.54%
hr 15.7 81.01 % 82.64%
hr 15.8 81.25% 83.00%
hr 16.0 81.75% 83.55% 84.73%
hr 16.2 82.10% 83.94%
hr 16.3 82.45% 84.35%
hr 16.5 83.04% 84.90%
hr 16.7 83.39% 85.24%
hr 16.8 83.78% 85.65%
hr 17.0 84.17% 86.04%
hr 17.2 84.55% 86.49%
hr 17.3 85.03% 86.91 hr 17.5 85.45% 87.30%
hr 17.7 85.76% 87.72%
hr 17.8 86.15% 87.96%
hr 18.0 86.60% 88.55% 89.49%
hr 18.2 86.89% 88.66%
hr 18.3 87.31 % 89.04%
hr 18.5 87.58% 89.29%
hr 18.7 88.06% 89.83%
hr 18.8 88.48% 90.16%
hr 19.0 88.87% 90.37%
hr 19.2 89.17% 90.75%
hr 19.3 89.43% 90.99%
hr 19.5 89.87% 91.47%
hr 19.7 90.23% 91.84%
hr 19.8 90.49% 91.96%
hr 20.0 90.63% 92.18%
hr 20.2 91.06% 92.55%
hr 20.3 91.18% 92.91 hr 20.5 91.48% 92.93%
hr 20.7 91.64% 93.32%
hr 20.8 92.10% 93.58%
hr 21.0 92.37% 93.89%
hr 21.2 92.42% 93.94%
hr 21.3 92.79% 94.23%
hr 21.5 92.93% 94.44%
hr 21.7 93.04% 94.57%
hr 21.8 93.28% 94.82%
hr 22.0 93.59% 95.30%
hr 22.2 93.61 % 95.34%
hr 22.3 94.01 % 95.57%
hr 22.5 94.10% 95.90%
hr WO 01/16582 CA 02383906 2002-02-27 pCT/US00/23800 Time Floatin Trian 1e TPAM 32m HPLC
Method 22.7 94.40% 96.02%
hr 22.8 94.46% 96.15%
hr 23.0 94.65% 96.19%
hr 23.2 94.88% 96.52%
hr 23.3 95.09% 96.82%
hr 23.5 95.28% 96.93%
hr 23.7 95.50% 97.04%
hr 23.8 95.70% 97.14%
hr 24.0 ~ - - 95.80% 97.52% 98.72%
hr Second Order Derivative Spectral Analysis Method In accordance with an embodiment of the present invention, scattering problems associated with in situ dissolution methods are reduced by calculating a second derivative of the spectra, subtracting an initial noise offset from the second derivative. The resultant difference value is then proportional to the amount of analyte dissolved. In order to obtain a plot of percent active agent dissolved versus time, the second derivative of the LJV spectra of the dissolution bath is first calculated.
The derivative of the spectra at a given point (i) is estimated by determing the slope of a straigth line which interconnects a previous spectral data point (i-1) and a next spectral data point (i+1). As shown in Figure 21, this line approximates the derivative at that point because the slope of the line between the points (i-1) and (i+1) is nearly the same (parallel) to the tangent line at the spectral data point (i).
Therefore, as shown in Figure 22, the derivative at any given point in the spectra can be estimated by calculating the slope between the previous data point and the next data point. This slope between two points can be more easily expressed as SLOPE = (y2-yl) .
(x2 - x1) Turning to Figure 22, the derivative of the point (284nm) is calculated by the equation Derivative@284nm = Absorbance@286nm-Absorbance@282nm . den this calculation is 286nm - 282nm carried out for each data point of the spectral plot, the derivative of the spectra is generated as shown in Figure 23.
5b rcT~rsoon3soo In accordance with the present invention, a second derivative of the spectra is taken in order to to correct for scattering. Since the second derivative represents the rate of change of the rate of change of the function, it will only represent spectral characteristics where a peak is present. Since the scattering interference causes a baseline offset with a variable slope, the second derivative removes this interference. By integrating the area under (and above) the second derivative, using a trapezoidal approximation, a value that is characteristic of the amount of analyte in the scattering matrix can be developed.
In order to correct for system noise, an initial noise offset is subtracted from the plot of the second order derivative of the spectral plot. The initial noise offset is set equal to the value of the second order derivative at a time t=0, which is a time just before the sample is placed in the dissolution vessel.
Example 7 In order to demonstrate that the method in accordance with the present invention provides a spectral plot that is largely unaffected by scattering interference, the scattering of a pharmaceutical matrix was simulated by using a photometric standard (turbidity standard) to create an interferance in the spectral observation of a dilute tramadol HCl solution. This experiment was performed using an HP 8452A PDA Spectrophotometer manufactured by Hewlett Packard as the CCD. This Spectrophotometer is a card-type CCD which is mounted within a PCB slot in a computer equipped with a Pentium~ processor.
The experiment was conducted by scanning a dilute tramadol standard, and then adding small amounts of turbidity standard to the sample between scans. The resultant W spectra shown in Figure 24 are typical for a drug substance in the presence of a scattering matrix (polymer).
The data set forth below in tables 9, 10, 11, and 12 regarding the turbidity interference results in the analysis of Tramadol HCL for 0, 1, 2, and 3 drops of turbidity standard respectively are plotted in Figure 24.
TABLE 9: 0 drops of turbidity standard Wavelen th nm Absorbance AU
220 3.41 E-01 222 3.20E-01 224 2.88E-01 226 2.52E-01 228 2.07E-01 230 1.56E-01 232 1.06E-01 234 6.52E-02 236 3.79E-02 238 2.29E-02 240 1.62E-02 242 1.41 E-02 244 1.40E-02 246 1.50E-02 248 1.68E-02 250 1.91 E-02 252 2.22E-02 254 2.59E-02 256 3.09E-02 258 3.67E-02 260 4.33E-02 262 5.12E-02 264 5.99E-02 266 6.77E-02 268 7.56E-02 270 8.45E-02 272 8.97E-02 274 8.71 E-02 276 8.30E-02 278 8.22E-02 280 7.36E-02 282 5.28 E-02 284 3.07E-02 286 1.69E-02 288 1.07E-02 290 8.10 E-03 292 7.13E-03 294 6.61 E-03 296 6.52E-03 298 6.42E-03 300 6.30E-03 TABLE 10: 1 drop of turbidity standard Wavelen th nm Absorbance AU
220 0.621536 Wavelen th nm Absorbance AU
222 0.601105 224 0.57312 226 0.53894 228 0.491302 230 0.430893 232 0.368729 234 0.315384 236 0.27504 238 0.24736 240 0.228699 242 0.215378 244 0.204971 246 0.196899 248 0.190292 250 0.185272 252 0.181839 254 0.179779 256 0.179779 258 0.180923 260 0.183319 262 0.187653 264 0.192978 266 0.197342 268 0.201492 270 0.206879 272 0.209381 274 0.20253 276 0.19426 278 0.189087 280 0.176407 282 0.152115 284 0.126846 286 0.10997 288 0.100723 290 9.53E-02 292 g.16E-02 294 8.85E-02 296 -- g_60E-02 -298 - 8.37E-02 300 8.15E-02 TABLE 11: 2 drops of turbidity standard Wavelen th nm Absorbance AU
220 1.0013 222 0.982758 224 0.960892 WO 01/16582 CA 02383906 2002-02-27 pCT/pS00/23800 Wavelen th nm Absorbance AU
226 0.933365 228 0.884766 230 0.814987 232 0.739136 234 0.669495 236 0.612488 238 0.568283 240 0.533356 242 0.504379 244 0.479553 246 0.458557 248 0.440186 250 0.424911 252 0.412064 254 0.40155 256 0.394394 258 0.388809 260 0.38504 262 0.384399 264 0.385147 266 0.38446 268 0.383331 270 0.383667 272 0.382248 274 0.36972 276 0.355362 278 0.101 280 0.325882 282 0.296631 284 0.267014 286 0.245743 288 0.232315 290 0.222961 292 0.215332 .294 0.208725 296 0.202652 298 0.197205 300 0.192017 TABLE 12: 3 drops of turbidity standard Wavelen th nm Absorbance AU
220 1.33568 222 1.32117 224 1.30655 226 1.28862 228 1.24454 Wavelen th nm Absorbance AU
230 1.17163 232 1.08739 234 1.00568 236 0.935791 238 0.877228 240 0.828064 242 0.785416 244 0.748138 246 0.715591 248 0.68631 250 0.661438 252 0.640198 254 0.621689 256 0.607681 258 0.595795 260 0.586044 262 0.580704 264 0.576675 266 0.571274 268 0.565384 270 0.560547 _ 0.55574 -274 0.537399 _. :. 276- - 0.517441 278 0.500427 280 0.476944 282 0.443085 284 0.409012 286 0.383759 288 0.366577 290 0.353027 292 0.341568 294 0.331436 296 0.322189 298 0.313507 _ 0.305374 The amount of analyte was then quantitated using two methods, a standard single point baseline correction, and a 2°d derivative function in accordance with the present invention. The results are sumarized in the table below .
Amount of Turbidity Baseline Subtraction Area of f'(x) Standard 272 nm - 304 nm 0 dro 0.083 0.018 1 dro 0.132 _ 0.018 2 dro 0.200 0.018 3 dro 0.266 0.018 D 46.81 % 0.90 The data in Table 13 demonstrates that the second derivative method in accordance with the present invention provides values that are largely unaffected by how much turbidity standard is added, as is demonstrated by the very low RSD (relative standard deviation). As one of skill in the art will appreciate, a low RSD value (i.e., standard deviation/avg. of values) indicates that there is very little deviation between the measured values despite the change in turbidity. In contrast, the RSD for the baseline subtraction method is significantly greater, indicating that the turbidity of the solution has a much greater affect on measured values. This is significant, because it is desirable to accurateiy quantify the amount of drug dissolved in the dissolution media in a dynamic matrix enviroment, in this case, a sample submerged in a dissolution medium replete with the debris from the partially dissolved sample.
It should be noted, however, that the matrix interference in this experiment is simplifed considerably due to the fact that the particle size of the polymer is uniform.
In an actual dissolution, the polymer size would be quite variable. Nevertheless, this test indicates that the second order derivative methods are significantly less affected by turbidity than a conventional baseline subtraction method.
As one of ordinary skill in the art will appreciate, a variety of programs known in the art can be used to calculate a second derivative, or can be readily programed by a computer programmer. In fact, the HP 8452A PDA spectrophotometer described above includes a built in function that could alternatively be used to calculate the first and second derivative of an acquired spectrum.
Example 8 In order to evaluate the effectiveness of the present invention in an actual dissolution vessel, dissolution data obtained by the HPLC method is compared with dissolution data obtained in situ in accordance with the present invention in Figure 25. The HPLC data is the same data referenced above in connection with Example 6. The in situ data used was generated in the same manner as the data referenced above in connection with Example 6.
The dissolution data obtained by the HPLC method at 1 , 2, 12, 18, and 24 hours in the manner set forth above is plotted again in Figure 25. Figure 25 also shows a plot of a second order derivative of the in-situ generated spectrum over a period from 0 to 24 hours, sampled every 10 minutes. As shown in Figure 25, the second order derivative function exhibits an initial offset at t=0 , which is a time just before the dosage unit is added to the vessels. This initial dissolved deviation is the result of the integration of the initial noise of the system, which is enhanced significantly by the 2°d derivative calculation. In the particular example in Figure 25, the initial value is approximately 3% at time t = 0.
In accordance with the present invention, this initial noise offset (the 2°d derivative of the value of the spectra at t = 0) is subtracted from all future measurements, so that the curve will correlate well with the HPLC sampling data. This corrected 2°d derivative was then used to recaculate both the accuracy and precision experiments for the 12 mg and 24 mg hydromorphone HPLC data set forth above.
Figure 26 shows an intermediate precision plot of the 12 mg hydromorphone capsule described above. Plots T1 and T2 are both plots of the dissolution of the 12 mg capsule described above conducted in situ with the equipment described above. In fact, T1 was generated from the same spectral data as the in situ plots of Figure 17.
However, T1 and T2 are derived from data generated by different technicians performing identical measurements on the same apparatus on different days. The data was then processed according to the floating triangle method to produce plots T1 and T2.
Figure 27 shows also shows an intermediate precision plot of the 12 mg hydromorphone capsule as described above. Plots T1' and T2' were generated with the 2d derivative baseline corrected method from the identical spectral data as plots T1 and T2, respectively. As plots T1' and T2' were generated from the same data as plots T1 and T2 respectively, the differences between the plots of Figures 26 and 27 are due solely to the different processing methods. A
comparison of Figures 26 and 27 clearly demonstrates that the plots generated with the baseline corrected second derivative method are at least as reproducible as the plots of the same data with the floating triangle method.
Figures 28 and 29 similarly show intermediate precision plots of the in situ dissolution of the 24 mg hydromorphone capsule described above. The spectral data was generated in the same manner as described above with respect to Example 6. As with Figure 26, plots T3 and T4 in Figure 28 were derived from data generated by different technicians performing identical measurements on the same apparatus on different days, and the data was processed according to the floating triangle method to produce plots T3 and T4. Plots T3' and T4' in Figure 29 were generated with the 2d derivative baseline corrected method from the identical spectral data as plots T3 and T4 of Figure 28, respectively. A comparison of Figures 28 and 29 demonstrates that the plots generated with the baseline corrected second derivative method are at least as reproducible as the plots of the same data with the floating triangle method.
Figure 30 illustrates a 12 mg accuracy validation which compares HPLC data generated as described in Example 6 with plots T1 (floating triangle method) and T1' (baseline corrected 2d derivative method). Figure 31 similarly illustrates a 24 mg accuracy validation which compares the HPLC data with plots T3 and T3' in Figures 28 and 29, respectively. Both Figure 30 and Figure 31 demonstrate that the baseline corrected 2d derivative method more closely correlates to the HPLC data.
The underlying data for Figures 25, 30, and 31 with regard to the baseline corrected second derivative plot is set forth below in Tables 14 and 15:
Table 14 Time Baseline CorrectionBaseline Corrected 12m 2nd Deriv 0.0 -1.58% 0.00%
hr 0.2 7.36% 5.62%
hr 0.3 10.87% 8.84%
hr 0.5 12.66% 10.78%
hr Time Baseline CorrectionBaseline Corrected 12m 2nd Deriv 0.7 hr 14.30% 12.61 0.8 hr 15.66% 13.74%
1.0 hr 17.23% 15.23%
1.2 hr 18.71 % 16.63%
1.3 hr 20.03% 18.05%
1.5 hr 21.39% 19.24%
1.7 hr 22.76% 20.71 1.8 hr 24.08% 21.95%
2.0 hr 25.46% 23.39%
2.2 hr 26.75% 24.71 2.3 hr 28.49% 26.11 2.5 hr 30.19% 27.22%
2.7 hr 31.58% 27.87%
2.8 hr 32.86% 29.50%
3.0 hr 33.94% 30.61 3.2 hr 35.63% 31.83%
3.3 hr 35.99% 32.31 3.5 hr 37.17% 33.56%
3.7 hr 38.38% 34.56%
3.8 hr 39.58% 36.12%
4.0 hr 40.83% 37.02%
4.2 hr 42.20% 38.31 4.3 hr 43.42% 39.21 4.5 hr 44.70% 40.19%
4.7 hr 45.93% 41.25%
4.8 hr 47.14% 42.24%
5.O hr 46.75% 43.34%
5.2 hr 47.48% 43.88%
5.3 hr 48.46% 45.29%
5.5 hr _ .49.88% 46.53%--5.7 hr 51.10% 47.26%
5.8 hr 52.29% 47.91 6.0 hr 53.57% 49.20%
6.2 hr 54.65% 50.21%
6.3 hr 55.78% 1.04 %
6.5 hr 56.87% _ _ 52.22%
6.7 hr 58.00% 53.05%
6.8 hr 59.03% 54.11 7.0 hr 60.01 % 55.16%
7.2 hr 61.08% 56.02%
7.3 hr 61.99% 57.00%
7.5 hr 63.12% 58.17%
7.7 hr 64.31 % 59.07%
7.8 hr 65.31 % 60.01 8.0 hr 66.19% 60.36%
8.2 hr =66.77% 61.78% -8.3 hr 67.31 % 62.29%
8.5 hr 68.28% 63.83%
Time Baseline CorrectionBaseline Corrected 12m 2nd Deriv 8.7 hr 69.47% 64.08%
8.8 hr 70.56% 64.83%
9.0 hr 71.85% 65.90%
9.2 hr 72.91 % 66.45%
9.3 hr 73.75% 67.11 9.5 hr 74.73% 67.90%
9.7 hr 75.63% 68.76%
9.8 hr 76.20% 69.89%
10.0 77.33% 70.42%
hr 10.2 78.69% 70.86%
hr 10.3 80.03% 71.83%
hr 10.5 80.88% 72.62%
hr 10.7 81.90% 73.05%
hr 10.8 82.96% 73.65%
hr 11.0 83.60% 74.26%
hr 11.2 83.89% 75.35%
hr 11.3 84.66% 76.36%
hr 11.5 85.16% 76.46%
hr 11.7 85.62% 77.48%
hr 11.8 86.19% 77.71 hr 12.0 87.13% 78.84%
hr 12.2 ~ 87.78% 79.23%
hr 12.3 88.79% 79.80%
hr 12.5 89.90% . $p.32%
hr 12.7 ~ 90.59% 80.50%
hr 12.8 91.40% 81.43%
hr 13.0 92.08% 81.79%
hr 13.2 92.92% 82.08%
hr 13.3 __ 83.41 hr 92.77%
13.5 92.71 % 83.86%
hr 13.7 92.90% 83.99%
hr 13.8 93.12% 84.90%
hr 14.0 93.71 % 85.66%
hr ~4.2 - 94.24% 85.88%
hr -14.3 94.81 % 85.99%
hr 14.5 95.36% 86.58%
hr 14.7 95.59% 87.11 hr 14.8 95.97% 87.31 hr 15.0 96.43% 88.13%
hr 15.2 97.01 % 88.08% -_ hr 15.3 87.36% 88.41 hr 15.5 97.84% 88.75% -hr 15.7 98.27% 89.26%
hr 15.8 98.60% 89.68% _ _ hr 16.0 99.04% 89.99/0 hr 16.2 99.17% 90.50%
hr _ 16.3 99.46% 90.30%
hr ~6.5 ~ 100.04% 90.80% -hr Time Baseline CorrectionBaseline Corrected 12m 2nd Deriv 16.7 100.21 % 91.23%
hr 16.8 100.41 % 91.54%
hr 17.0 100.85% 91.74%
hr 17.2 101.10% 92.17%
hr 17.3 101.43% 92.10%
hr 17.5 101.77% 92.64%
hr 17.7 101.95% 92.78%
hr 17.8 102.04% 93.34%
hr 18.0 102.50% 93.85%
hr 18.2 102.67% 93.51 hr 18.3 102.87% 93.69%
hr 18.5 103.09% 93.95%
hr 18.7 103.20% 94.00%
hr 18.8 103.31 % 94.26%
hr 19.0 103.87% 94.31 hr 19.2 104.03% 94.76%
hr 19.3 104.16% 94.81 hr 19.5 104.62% 95.16%
hr 19.7 104.75% 94.86%
hr 19.8 105.00% 95.27%
hr 20.0 105.18% 95.81 hr 20.2 ~ 105.61 % 95.62 hr %
20.3 -105.95% _ hr 95.94%-20.5 106.11 % 96.00%
hr 20.7 106.09% 96.34%
hr 20 -106.42% 96.76%
.8 hr _ 106.54% 96.82%
21.0 hr 21.2 106.82% 96.78%
hr 21.3 107.04% 96.73%
hr 21.5 107.25% 97.06%
hr 21.7 --107.46% _ hr 97.07% _.
21.8 107.62% 97.03%
hr 22.0 107.80% 96.99%
hr 22.2 108.09% 97.11 hr 22.3 108.18% 98.16%
hr 22.5 108.16% 97.53%
hr 22. . -108.03% gg.02%
7 hr _ ~ ~ 08.32% 97.95%
22.8 hr 23.0 108:69% 97.75%
hr 23.2 :108:71 % 98.07%
hr 23.3 108.92% 98.94%
hr 23.5 1-8.81 % 98.04%
hr 23.7 109.12% 98.44%
hr 23.8 109.16% 98.20%
hr 24.0 109.48% 98.46%
hr Table 15 Time Baseline CorrectionBaseline Corrected 24m 2nd Deriv 0.0 hr 0.06% 0.00%
0.2 hr 7.27% 6.86%
0.3 hr 9.58% 9.36%
0.5 hr 11.22% 10.59%
0.7 hr 12.69% 12.30%
0.8 hr 14.14% 13.42%
1.0 hr 15.45% 14.99%
1.2 hr 16.78% 16.12%
1.3 hr 18.03% 17.17%
1.5 hr 19.17% 18.65%
1.7 hr 20.40% 19.87%
1.8 hr 21.55% 21.02%
2.0 hr 22.78% 22.03%
2.2 hr 23.91 % 23.42%
2.3 hr 25.11 % 24.71 2.5 hr 26.39% 25.76%
2.7 hr 27.47% 27.05%
2.8 hr 28.71 % 28.34%
3.0 hr 29.86% 29.47%
3.2 hr 31.08% 30.99%
3.3 hr ~ 32.23% 31.99%
3.5 hr 33.46% 33.01 3.7 hr ~.~% 34.32%
3.8 hr 35.86% 35.44%
4.0 hr 37.03% 36.82%
4.2 hr 38.24% 37.96%
4.3 hr 39.42% 39.16%
4.5hr 40.66% 40.64%
4.7 hr 41.74% 41.72%
4.8 hr - 42.99% 42.79 %
5.0 hr 43.96% _ 44.2 3%
5.2 hr 45.16% _ 45.47%
5.3 hr 46.31 % 46.63%
5.5 hr = 47.62% 47.71 5.7 hr 48 49.17%
.66%
5.8 hr _ 50.23% -. _ 49.70%
6.0 hr 50.76% 51.28 %
6.2 hr . 51.94% _ 52.47% -6.3 hr 53.03% 53.44%
6.5 hr 54.06% 54.49%
6.7 hr 55.15% 55.66%
6.8 hr _ 56.23% . 56.64%
7.0 hr 57.26% 57.37%
7.2 hr 58.39% 58.39%
7.3 hr 59.43% 59.54%
7.5 hr 60.43% 60.40%
7.7 hr 61.42% 61.46%
7.8 hr 62.39% 62.72%
Time Baseline CorrectionBaseline Corrected 24m 2nd Deriv 8.0 hr .63.26% - 63.56%
8.2 hr 64.24% 64.52%
8.3 hr 64.93% 65.99%
8.5 hr 66.01 % 66.77%
8.7 hr 67.04% 67.44%
8.8 hr 67.98% 68.39%
9.0 hr 68.87% 69.17%
9.2 hr 69.64% 70.16%
9.3 hr 70.68% 71.18%
9.5 hr 71.41% 71.91%
9.7 hr 72.13% 72.65%
9.8 hr 72.87% 73.41 10.0 73.66% 74.25%
hr 10.2 74.32% 74.91 hr 10.3 75.30% 75.49%
hr 10.5 76.04% 76.06%
hr 10.7 76.77% 76.95%
hr 10.8 77.51 % 77.36%
hr 11.0 78.08% 77.90%
hr 11.2 78.70% 78.61 hr 11.3 79.28% 79.37%
hr .5 hr 79.86% 80.11 _ 80.39% 80.87%
11.7 hr 11.8 81.01% 81.56% -hr -12.0 - 81.46% 82.17% -hr -12.2 - 82.00% 82.89%
hr 12.3 -82.55% 3% -hr- 83.2 12.5 83.18% _ hr 83.49%.
12.7 ...$3.74% 83.82%
hr -12.8 84.18% 84.45%
hr 13.0 84.73% 85.30%
hr 13.2 85.15% 85.57%
hr 13.3 85.64% 85.70%
hr 13.5 85.92% 86.51 hr %
13.7 86.29% _ hr 86.77%
13.8 86.81 % 87.12%
hr 14.0 87.25% 88.13%
hr 14.2 87.57% 88.28%-hr 14.3 87.82% 88.93%
hr 14.5 88.16% 89.06%
hr 14.7 88.57% 89.39%
hr 14.8 88.88% 89.86% -hr 15.0 89.11 % 90.32%
hr 15.2 89.51 % 90.52%
hr 15.3 89.81 % 90.78%
hr 15.5 90.04% 91.08%
hr _ 15.7 90.24% 91.20%
hr 15.8 90.59% 91.42%
hr Time Baseline CorrectionBaseline Corrected 24m 2nd Deriv 16.0 90.94% 91.84%
hr 16.2 91.27% 92.12%
hr 16.3 91.35% 92.38%
hr 16.5 91.65% 92.73%
hr 16.7 91.88% 93.10%
hr 16.8 92.09% 93.30%
hr 17.0 92.35% 93.01 hr 17.2 92.64% 93.37%
hr 17.3 92.81 % 93.82%
hr 17.5 93.04% 93.92%
hr 17.7 93.15% 94.17%
hr 17.8 93.32% 94.48%
hr 18.0 93.56% 94.75%
hr 18.2 93.74% 94.71 hr 18.3 93.94% 95.20%
hr 18.5 .._..94,:U8% . g5.43%
hr 18.7 94.26% 95.34%
hr 18.8 94.43% 95.90%
hr 19.0 94.56% 95.46%
hr 19.2 94:68% 95.84%
hr 19.3 94.99% 95.98%
hr 19.5 95.14% 96.34%
hr 19.7 95.17% 96.39%
hr _ ~ 95.39% 96.59%
19.8 hr __ 95.52% 96.61 20.0 hr 20.2 95.68% 96.53%
hr 20.3 95.68% 97.16%
hr 20.5 95.96% 96.93%
hr 20.7 96.02% 97.25%
hr 20.8 96.16% 97.28%
hr 21.0 96.20% 97.32%
hr 21.2 96.46% . .. 87.42%
hr 21.3 , 86:48% 97.38%
hr 21.5 ~ 96.61 % 97.24%
hr 21.7 96.74% 97.56%
hr 21.8 96,81 % - -97.71 hr 22.0 96.94% 97.77%
hr 22.2 96.91 % 97.85%
hr 22.3 97.08% 98.16%
hr 22.5 97.12% gg.31%
hr 22.7 97. 98.12 hr 22% - %
22.8 _ _ hr 87:38% -- 88.33% - _.
23.0 , .:97.47% 98.57% - _ hr 23.2 97.46% 98.37%
hr 23.3 97.54% 98.46% -hr 23.5 97.71 % 98.64%
hr 23.7 97.68% g8.55%
hr 23.8 ' 97:78% ~ 98.67% _ hr Time~Baseline Correction 24mg I Baseline Corrected 2nd Deriv I
I 24.0 hr ~ 97.85% I 98.75%
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 S encompassed within the appended claims.
Claims (18)
1. A method for continuously measuring the release of a substance from a pharmaceutical dosage form comprising the steps of a) placing a pharmaceutical dosage form in a vessel containing a dissolution medium;
b) detecting a spectrum of the dissolution medium;
c) calculating a second derivative of each detected spectrum;
d) deriving an amount of the substance dissolved from the pharmaceutical dosage form from said second derivative.
b) detecting a spectrum of the dissolution medium;
c) calculating a second derivative of each detected spectrum;
d) deriving an amount of the substance dissolved from the pharmaceutical dosage form from said second derivative.
2. The method according to claim 1, wherein step (d) includes the step of subtracting from said second derivative the value of the spectrum just prior to performing step (a) to obtain a corrected second derivative value, said corrected second derivative being proportional to the amount of the substance dissolved from the pharmaceutical dosage form
3. The method according to claim 1, wherein the vessel has a mixing shaft disposed therein for mixing the dissolution medium.
4. The method according to claim 3, wherein said mixing shaft has paddles disposed thereon.
5. The method according to claim 3, wherein step b includes the step of detecting a spectrum of the dissolution medium utilizing a fiber optic probe disposed within the mixing shaft.
6. The method according to claim 3, wherein the fiber optic probe is disposed adjacent to a mixing shaft, wherein the mixing shaft is disposed within the vessel for mixing the dissolution medium.
7. The method according to claim 1, further comprising repeating steps b through d for a second substance in the pharmaceutical dosage form.
8. The method according to claim 1, further comprising repeating steps b through d a plurality of times as dissolution of the dosage form in the dissolution medium proceeds.
9. A method for continuously measuring the release of a substance from a pharmaceutical dosage form comprising the steps of:
a) placing a pharmaceutical dosage form in a vessel containing a dissolution medium;
b) detecting a spectrum of the dissolution medium;
c) identifying a wavelength range corresponding to a characteristic range of an analyte, wherein said characteristic range extends from x i to x n, and wherein the UV
spectrum is defined as a function f(x,y);
d) generating a baseline corrected function fl(x,y) which is equal to f(x,y) minus a lesser of y i and y n ;
e) calculating an area under the curve of fl(x,y) from x i to x n, said area under the curve defined as wherein delta "x" = abs(x n - x i);
f) calculating an area of a lower right triangle (ART), wherein ART is defined as g) subtracting ART from A.U.C. to obtain a measured peak area MPA of the analyte, said MPA being indicative an amount of analyte in the dissolution media; and h) repeating steps b through g on spectra detected at selected time intervals to calculate the amount of analyte in the dissolution media over time.
a) placing a pharmaceutical dosage form in a vessel containing a dissolution medium;
b) detecting a spectrum of the dissolution medium;
c) identifying a wavelength range corresponding to a characteristic range of an analyte, wherein said characteristic range extends from x i to x n, and wherein the UV
spectrum is defined as a function f(x,y);
d) generating a baseline corrected function fl(x,y) which is equal to f(x,y) minus a lesser of y i and y n ;
e) calculating an area under the curve of fl(x,y) from x i to x n, said area under the curve defined as wherein delta "x" = abs(x n - x i);
f) calculating an area of a lower right triangle (ART), wherein ART is defined as g) subtracting ART from A.U.C. to obtain a measured peak area MPA of the analyte, said MPA being indicative an amount of analyte in the dissolution media; and h) repeating steps b through g on spectra detected at selected time intervals to calculate the amount of analyte in the dissolution media over time.
10. The method according to claim 9 wherein the vessel has a mixing shaft disposed therein for mixing the dissolution medium.
11. The method according to claim 10, wherein said mixing shaft has paddles disposed thereon.
12. The method according to claim 10, wherein step b includes the step of detecting a spectrum of the dissolution medium utilizing a fiber optic probe disposed within the mixing shaft.
13. The method according to claim 9, wherein step b includes the step of detecting a spectrum of the dissolution medium utilizing a fiber optic probe disposed within the vessel.
14. The method according to claim 13, wherein the fiber optic probe is disposed adjacent to a mixing shaft, wherein the mixing shaft is disposed within the vessel for mixing the dissolution medium.
15. 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 vessel for immersing a pharmaceutical dosage form in a dissolution medium;
a probe disposed within the vessel and immersed in the dissolution medium, the probe including a light emitting diode and a photodetector disposed on opposing sides of a flow cell formed in the probe;
a processor coupled to the probe.
a vessel for immersing a pharmaceutical dosage form in a dissolution medium;
a probe disposed within the vessel and immersed in the dissolution medium, the probe including a light emitting diode and a photodetector disposed on opposing sides of a flow cell formed in the probe;
a processor coupled to the probe.
16. A probe comprising an elongated shaft having an opening formed therein, the probe including a light emitting diode and a photodetector disposed on opposing sides of the opening.
17. The probe of claim 16, wherein the opening is a flow cell.
18. A method for achieving a specified energy level on a spectrometer, comprising:
a) acquiring data from a detector using a first integration time and obtaining a relative energy value as a function thereof;
b) comparing the relative energy value with a target relative energy value and, based upon said comparision, either identifying the integration time as an accepted integration time, incrementing the integration time, or decrementing the integration time;
c) repeating steps a and b if the accepted integration time has not been identified.
a) acquiring data from a detector using a first integration time and obtaining a relative energy value as a function thereof;
b) comparing the relative energy value with a target relative energy value and, based upon said comparision, either identifying the integration time as an accepted integration time, incrementing the integration time, or decrementing the integration time;
c) repeating steps a and b if the accepted integration time has not been identified.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US15144399P | 1999-08-30 | 1999-08-30 | |
| US60/151,443 | 1999-08-30 | ||
| PCT/US2000/023800 WO2001016582A1 (en) | 1999-08-30 | 2000-08-30 | In situ methods for measuring the release of a substance from a dosage form |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2383906A1 true CA2383906A1 (en) | 2001-03-08 |
Family
ID=22538787
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002383906A Abandoned CA2383906A1 (en) | 1999-08-30 | 2000-08-30 | In situ methods for measuring the release of a substance from a dosage form |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1210583A4 (en) |
| JP (1) | JP2003508748A (en) |
| AU (1) | AU7337500A (en) |
| CA (1) | CA2383906A1 (en) |
| WO (1) | WO2001016582A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1373863A4 (en) * | 2001-03-27 | 2005-01-26 | Euro Celtique Sa | Atr crystal device |
| US7620576B1 (en) | 2003-01-21 | 2009-11-17 | Trading Technologies International, Inc. | Method and apparatus for providing order queue information |
| US7024955B2 (en) | 2003-03-01 | 2006-04-11 | Symyx Technologies, Inc. | Methods and systems for dissolution testing |
| US7809628B1 (en) | 2003-05-30 | 2010-10-05 | Trading Technologies International Inc. | System and method for estimating order position |
| JP2005172779A (en) * | 2003-12-10 | 2005-06-30 | Semiconductor Res Found | Method and apparatus for measuring bacteria, virus and toxic substance by irradiation with electromagnetic wave |
| GB0524225D0 (en) * | 2005-11-29 | 2006-01-04 | Amersham Biosciences Ab | Methods and apparatus for detecting and measuring the concentration of a substance in a solution |
| JP2009063335A (en) * | 2007-09-05 | 2009-03-26 | Fujifilm Corp | Measuring method for interaction of physiologically active substance with substance to be examined |
| MY179050A (en) | 2008-04-04 | 2020-10-26 | Colgate Palmolive Co | Analysis of substrates having agents deposited thereon |
| JP2009075134A (en) * | 2009-01-05 | 2009-04-09 | Junichi Nishizawa | Identification device for bacterium or toxic substance |
| JP5773914B2 (en) * | 2011-03-11 | 2015-09-02 | ディステック，インコーポレーテッド | Centrally controlled modular motorized testing |
| CN102721796A (en) * | 2012-06-27 | 2012-10-10 | 浙江省中医药研究院 | Experimental device for simulating local drug release behavior of medicine and application thereof |
| JP6635363B2 (en) * | 2014-10-24 | 2020-01-22 | 京都府公立大学法人 | Method for discriminating tumor site, device for discriminating tumor site |
| WO2016079797A1 (en) * | 2014-11-18 | 2016-05-26 | 日本メクトロン株式会社 | Inline concentration measurement probe and concentration measurement system |
| CN109975274B (en) * | 2019-04-16 | 2024-01-23 | 北京科技大学 | Online rapid detection device for silicon content of molten iron of blast furnace |
| WO2022091697A1 (en) * | 2020-10-26 | 2022-05-05 | ソニーグループ株式会社 | Information processing device, information processing method, and program |
| CN112816446B (en) * | 2020-12-24 | 2022-02-01 | 四川长虹电器股份有限公司 | Method for detecting powder decay of fluorescent wheel based on fluorescence spectrum |
| CN117730247A (en) * | 2021-07-12 | 2024-03-19 | Isa制药有限公司 | Improved quantification of substances in complex mixtures |
| CN117783459A (en) * | 2024-02-28 | 2024-03-29 | 沈阳科惠生物医药科技有限公司 | Drug dissolution curve determination method and system |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4335438A (en) * | 1980-04-17 | 1982-06-15 | Smolen Victor F | Method and apparatus for automatic dissolution testing of products |
| US4740709A (en) * | 1986-04-10 | 1988-04-26 | The United States Of America As Represented By The Department Of Health And Human Services | Method of sensing fluid properties independent of bubble concentrations |
| US5070874A (en) * | 1990-01-30 | 1991-12-10 | Biocontrol Technology, Inc. | Non-invasive determination of glucose concentration in body of patients |
| WO1995023329A1 (en) * | 1994-02-25 | 1995-08-31 | Distek Inc. | Dissolution testing apparatus |
| US5679954A (en) * | 1994-11-14 | 1997-10-21 | Soloman; Sabrie | Non-destructive identification of tablet and tablet dissolution by means of infared spectroscopy |
| AU729814B2 (en) * | 1996-06-04 | 2001-02-08 | Delphian Technology Inc. | Improvements in detection systems and methods for predicting the dissolution curve of a drug from a pharmaceutical dosage form |
-
2000
- 2000-08-30 AU AU73375/00A patent/AU7337500A/en not_active Abandoned
- 2000-08-30 CA CA002383906A patent/CA2383906A1/en not_active Abandoned
- 2000-08-30 EP EP00961420A patent/EP1210583A4/en not_active Withdrawn
- 2000-08-30 WO PCT/US2000/023800 patent/WO2001016582A1/en active Application Filing
- 2000-08-30 JP JP2001520088A patent/JP2003508748A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP1210583A1 (en) | 2002-06-05 |
| EP1210583A4 (en) | 2004-08-11 |
| JP2003508748A (en) | 2003-03-04 |
| WO2001016582A1 (en) | 2001-03-08 |
| WO2001016582A9 (en) | 2002-09-12 |
| AU7337500A (en) | 2001-03-26 |
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