Revision Bulletin
`Official January 1, 2011
`
`.
`
`Clonidine Transdermal System
`
`DEFINITION
`Clonidine Transdermal System contains NLT 80.0% and NMT
`120.0% of the labeled amount of clonidine (C9H9Cl2N3).
`[NOTE—Throughout the following procedures, avoid the use of
`tetrahydrofuran stabilized with butylated hydroxytoluene
`(BHT). In the presence of peroxides, BHT may react with
`clonidine, producing impurity peaks.]
`
`IDENTIFICATION
`• A. INFRARED ABSORPTION Æ197Kæ
`Buffer solution: 242.28 g/L of tris-(hydroxymethyl)ami-
`nomethane in water. Adjust with dilute hydrochloric acid to
`a pH of 9.2.
`Sample: Carefully peel the release liner from each Trans-
`dermal System, and place a number of Transdermal Systems
`equivalent to 25 mg of clonidine into a 50-mL screw-capped
`centrifuge tube. Add 5 mL of chloroform, and mix on a
`vortex mixer for 5 min. Allow to stand for 30 min, and mix
`intermittently on a vortex mixer. Transfer the chloroform so-
`lution to another 50-mL centrifuge tube, and wash the resi-
`due with an additional 3 mL of chloroform, combining the
`extracts. Add 2 mL of 0.5 N hydrochloric acid to the extract,
`mix on a vortex mixer for 1 min, and centrifuge at about
`1000 rpm for 4 min. Remove and discard the bottom chlo-
`roform layer. Extract the aqueous layer with 4 mL of chloro-
`form. Centrifuge at 1000 rpm for an additional 5 min, and
`again discard the bottom chloroform layer. Add 5 mL of
`Buffer solution and 3 mL of methylene chloride. Mix on a
`vortex mixer for 1 min. Centrifuge at 1000 rpm for 4 min.
`Transfer the bottom methylene chloride layer into a 100-mL
`beaker, and dry the methylene chloride with anhydrous so-
`dium sulfate (about 1/4 liquid height). Decant and evapo-
`rate to dryness with a stream of nitrogen. Dry at 105(cid:176) for 30
`min, and allow to cool in a desiccator.
`Analysis: Determine the IR spectrum of the Sample solution
`and USP Clonidine Hydrochloride RS in the wavelength re-
`gion of 3500–600 cm-1 .
`• B. The retention time of the major peak of the Sample solu-
`tion corresponds to that of the Standard solution, as obtained
`in the Assay.
`
`ASSAY
`• PROCEDURE
`Buffer solution: 2.5 mL of triethylamine in 1 L of water.
`Adjust with phosphoric acid to a pH of 3.0.
`Mobile phase: Acetonitrile and Buffer solution (60:40).
`[NOTE—Stir the solution for 30 min.]
`Diluent: Tetrahydrofuran and methanol (1:1)
`System suitability solution: 250 mg/mL of USP Clonidine RS
`and 10 mg/mL of USP Clonidine Related Compound B RS in
`Diluent
`Standard stock solution: 1 mg/mL of USP Clonidine RS in
`tetrahydrofuran
`Standard solutions: Prepare a minimum of four Standard
`solutions from the Standard stock solution in Diluent that
`bracket the expected clonidine concentration in the sample.
`The standard concentrations should be within the range of
`50–300 mg/mL. [N OTE—The Standard solutions are stable for
`up to 2 days if stored at 4(cid:176).]
`Sample solution: 357 mg/mL of clonidine prepared as fol-
`lows: remove each Transdermal System from its package,
`discard the release liner from each system, and transfer into
`a 50-mL centrifuge tube with a Teflon-lined screw cap. Add
`the appropriate volume of tetrahydrofuran as listed in the
`table below.
`
`Clonidine 1
`
`For systems containing about 2.5 mg of clonidine
`For systems containing about 5.0 mg of clonidine
`For systems containing about 7.5 mg of clonidine
`
`7.0 mL
`14.0 mL
`21.0 mL
`
`Mix vigorously on a vortex mixer until the systems are
`washed down and fully submerged in the tetrahydrofuran.
`Let the systems soak in tetrahydrofuran for about 5 min,
`and mix on a vortex mixer until the systems are completely
`delaminated. Allow the systems to remain submerged for
`an additional 60 min, mixing on a vortex mixer every 30
`min. Add methanol in a volume equal to the volume of
`tetrahydrofuran, and mix vigorously on a vortex mixer. The
`solution turns milky. Centrifuge for 10 min at 2000 rpm.
`Use the supernatant as the Sample solution.
`Chromatographic system
`(See Chromatography Æ621æ, System Suitability.)
`Mode: LC
`Detector: UV 210 and 242 nm
`[NOTE—The detector is programmed initially to 242 and
`switched to 210 nm after the elution of the clonidine
`peak but before the elution of the clonidine related com-
`pound B.]
`Column: 4.6-mm · 15-cm; packing L10
`Flow rate: 1 mL/min
`Injection size: 25 mL
`System suitability
`Sample: System suitability solution
`[NOTE—The relative retention times for clonidine and
`clonidine related compound B are 1.0 and 1.5,
`respectively.]
`Suitability requirements
`Resolution: NLT 2.0 between clonidine and clonidine re-
`lated compound B
`Capacity factor, k¢:
` NLT 0.6 for clonidine
`Tailing factor: NMT 3.0 for both clonidine and clonidine
`related compound B
`Relative standard deviation: NMT 2.0% for the
`clonidine peak area
`Analysis
`Samples: At least three Standard solutions that will bracket
`the expected sample concentration range and the Sample
`solution
`Calculate the peak response ratios of the analyte, and plot
`the results. Determine the linear regression equation of the
`standards by the mean-square method, and record the lin-
`ear regression equation and the correlation coefficient; it
`should be NLT 0.995.
`Calculate the percentage of the labeled amount of clonidine
`(C9H9Cl2N3) in the Transdermal System taken:
`Result = (CS/CU) · 100
`
`CS
`
`= concentration of clonidine from the linear regres-
`sion analysis (mg/mL)
`= nominal concentration of clonidine in Sample so-
`lution (mg/mL)
`Acceptance criteria: 80.0%–120.0%
`
`CU
`
`PERFORMANCE TESTS
`
`Change to read:
`• DRUG RELEASE Æ724æ
`•Test 1• (RB 1-Jan-2011)
`Medium: 0.001 M phosphoric acid; 80 mL for systems con-
`taining 5 mg or less of clonidine; 200 mL for systems con-
`taining more than 5 mg of clonidine
`
`ª 2010 The United States Pharmacopeial Convention All Rights Reserved.
`
`NOVARTIS EXHIBIT 2023
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 1 of 3
`
`

`

`2 Clonidine
`
`Times: 8, 24, 96, and 168 h
`Apparatus 7: Proceed as directed in the chapter, using the
`transdermal system holder-angled disk (see Figure 4a). The
`appropriate size of the holder, 1.42 or 1.98 inches, should
`be chosen based on the size of the system to prevent over-
`hang. Use 100-mL beakers for Medium volumes of 80 mL
`and 300-mL beakers for Medium volumes of 200 mL. Gen-
`tly press the Transdermal System to a dry, smooth, square
`piece of cellulose membrane, or equivalent, with the adhe-
`sive side against the membrane. Attach the membrane/sys-
`tem to a suitable inert sample holder with a Viton O-ring,
`or equivalent, so that the backing of the system is adjacent
`to and centered on the bottom of the sample holder. Trim
`the excess cellulose membrane with scissors. Suspend each
`sample holder from the arm of a reciprocating shaker so
`that each system is continuously immersed in a beaker con-
`taining the specified volume of Medium. The filled beakers
`are weighed and pre-equilibrated to 32.0 – 0.3(cid:176) before im-
`mersing the test sample. Agitate the sample in an up-down
`motion at a frequency of 30 cycles/min with an amplitude
`of 2.0 – 0.1 cm. The Medium must be added daily to the
`beakers during each interval to maintain sample immersion.
`At the end of each time interval, transfer the test sample to
`a fresh beaker containing the appropriate volume of Me-
`dium, weighed and pre-equilibrated to 32.0 – 0.3(cid:176).
`Mobile phase: 0.1% solution of triethylamine in a mixture
`of methanol and water (30:70). Adjust with phosphoric
`acid to a pH of 6.0 – 0.2.
`System suitability solution: 10 mg/mL of USP Clonidine RS
`in 0.001 M phosphoric acid
`Standard solutions: Prepare a minimum of four Standard
`solutions of USP Clonidine RS in 0.001 M phosphoric acid
`having known concentrations of clonidine similar to those
`of the Sample solutions.
`Sample solutions: At the end of each release interval, al-
`low the beakers to cool to room temperature and make up
`for evaporative Medium losses by adding Medium to obtain
`the original weight, then mix.
`Chromatographic system
`(See Chromatography Æ621æ, System Suitability.)
`Mode: LC
`Detector: UV 220 nm
`Column: 4.6-mm · 15-cm; packing L1
`Flow rate: 1.5 mL/min
`Injection size: 25 mL
`System suitability
`Sample: System suitability solution
`Suitability requirements
`Column efficiency: NLT 2000 theoretical plates
`Tailing factor: NMT 2.0
`Capacity factor: NLT 0.5
`Relative standard deviation: NMT 2.0%
`Analysis
`Samples: Standard solutions and Sample solutions
`Construct a standard curve of concentration (mg/mL) of
`clonidine in the Standard solutions versus peak area by lin-
`ear regression analysis. The correlation coefficient is NLT
`0.995. Calculate the release rate of clonidine:
`
`Result = CV/TA
`
`C
`
`= concentration of clonidine in the sample of the
`standard curve (mg/mL)
`= volume of the Medium (mL)
`V
`= time (h)
`T
`= area of the Transdermal System (cm2)
`A
`Tolerances: See Table 1.
`
`Revision Bulletin
`Official January 1, 2011
`
`Time
`(h)
`0–8
`8–24
`24–96
`96–168
`
`Table 1
`Time for Sampling
`(h)
`8
`24
`96
`168
`
`Release Rate
`(mg/h/cm 2)
`7.5–16.0
`1.5–4.6
`1.5–4.6
`1.5–3.3
`
`The release rate of clonidine (C9H9Cl2N3) from the Trans-
`dermal System, expressed as mg/h/cm 2 at the times speci-
`fied, conforms to Acceptance Table 1 in <724>.
`•Test 2: If the product complies with this test, the labeling
`indicates that it meets USP Drug Release Test 2.
`Medium: 0.01 N hydrochloric acid; 500 mL for systems la-
`beled as 0.1 mg/day, 900 mL for systems labeled as 0.2
`mg/day or 0.3 mg/day
`Apparatus 6: 100 rpm. Apply double-sided tape around
`the lower-most circumference of the cylinder, overlapping
`the ends to prevent peeling of the tape end from the cylin-
`der. Remove the outer layer of the tape. Attach the Trans-
`dermal System to the cylinder with the backing side
`against the double-sided tape and the longitudinal axis par-
`allel to the bottom of the cylinder. Carefully smooth the
`system to remove any air bubbles, and remove the release
`liner from the system. For systems requiring 500 mL of
`Medium, apply the double-sided tape to the system such
`that the bottom edge of each is NMT 2 mm from the
`bottom of the cylinder to prevent evaporation during the
`test from exposure to air. After setting the cylinder in the
`vessel, cover the vessel to minimize evaporation.
`Times: 6, 48, 96, and 168 h
`Buffer solution: 0.3% triethylamine in 0.025 M potassium
`phosphate monobasic. Adjust with phosphoric acid to a pH
`of 6.20 – 0.10.
`Mobile phase: Buffer solution and tetrahydrofuran (94:6)
`Standard solutions: Solutions containing 0.7, 3.0, 5.3, 7.5,
`and 9.8 mg/mL of USP Clonidine RS in Medium. A small
`amount of methanol (not exceeding 10% of the final vol-
`ume) can be used to solubilize clonidine.
`Sample solution: 1.5 mL aliquots of the solution under
`test. After sampling the last time point, measure the vol-
`ume of Medium remaining in the vessel.
`Chromatographic system
`(See Chromatography Æ621æ, System Suitability.)
`Mode: LC
`Detector: UV 210 nm
`Guard column: 3.0-mm · 4-mm; packing L1
`Analytical column: 4.6-mm · 15-cm; packing L1
`Flow rate: 1.0 mL/min
`Injection size: 50 mL
`System suitability
`Sample: 5.3 mg/mL of the Standard solution
`Suitability requirements
`Tailing factor: NMT 2.0
`Relative standard deviation: NMT 3.0%
`Analysis
`Samples: Standard solutions and Sample solutions
`Construct a standard curve of concentration (mg/mL) of
`clonidine in the Standard solutions versus peak area by lin-
`ear regression analysis. The correlation coefficient is NLT
`0.997. Calculate the release rate of clonidine:
`Calculate the volume loss rate in mL/h (L):
`L = [V - F + (N · 1.5)]/T
`
`V
`F
`N
`
`= initial volume of Medium (mL)
`= final volume of Medium (mL)
`= number of sampling time points
`
`ª 2010 The United States Pharmacopeial Convention All Rights Reserved.
`
`NOVARTIS EXHIBIT 2023
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 2 of 3
`
`

`

`Revision Bulletin
`Official January 1, 2011
`
`T
`
`= total elapsed time between start of run and final
`volume measurement (h)
`Calculate the volume (mL) at each sampling time adjusted
`for evaporation (Vadj):
`Vadj = V - (L · t
`
`C) - [(n - 1) · 1.5]
`
`tC
`
`= cumulative time for the sample withdrawal (6,
`48, 96, or 168 h)
`= sampling number (1, 2, 3, or 4 for the 6-, 48-,
`n
`96-, and 168-h sampling times, respectively
`Calculate the release rate of clonidine (mg/h/cm 2):
`Result = [(rU - b) · V adj]/(m · A · t
`
`i)
`
`rU
`= peak response from the Sample solution
`= y-intercept of the standard curve
`b
`= slope of the standard curve
`m
`= area of the system (cm2)
`A
`= interval time (h)
`ti
`Tolerances: See Table 2.
`
`Table 2
`
`Time for
`Sampling
`(h)
`6
`48
`96
`168
`
`Interval
`Time
`(h)
`6
`42
`48
`72
`
`Release Rate
`(mg/h/cm 2)
`7.6–12.0
`1.7–2.5
`2.0–2.9
`1.7–2.6
`
`Time
`(h)
`0–6
`6–48
`48–96
`96–168
`
` The release rate of clonidine (C9H9Cl2N3) from the Trans-
`dermal System, expressed as mg/h/cm 2 at the times speci-
`fied, conforms to Acceptance Table 1 in <724>.• (RB 1-Jan-2011)
`• UNIFORMITY OF DOSAGE UNITS Æ905æ:
` Meet the requirements
`IMPURITIES
`• ORGANIC IMPURITIES
`Mobile phase, Diluent, System suitability solution, Sample
`solution, and Chromatographic system: Proceed as di-
`rected in the Assay.
`Standard stock solution: 1 mg/mL of USP Clonidine Re-
`lated Compound B RS in tetrahydrofuran
`Standard solutions: Prepare a minimum of four Standard
`solutions in Diluent that bracket the expected clonidine re-
`lated compound B concentration in the sample. The stan-
`dard concentrations should be within the range of 0.2–10.0
`mg/mL.
`
`Clonidine 3
`
`[NOTE—The Standard solutions are stable for up to 2 days if
`stored at 4(cid:176).]
`Analysis
`Samples: At least three Standard solutions that will bracket
`the expected sample concentration range and the Sample
`solution.
`Measure the responses for the clonidine related compound
`B. Calculate the peak response ratios of the analyte, and
`plot the results. Determine the linear regression equation of
`the standards by the mean-square method, and record the
`linear regression equation and the correlation coefficient; it
`should be NLT 0.995. Determine the concentration of the
`clonidine related compound B.
`Calculate the amount, in mg/cm 2, of the clonidine related
`compound B in the portion of the Transdermal System
`taken:
`
`Result = CV/A
`
`C
`
`= concentration of clonidine related compound B
`from the linear regression analysis (mg/mL)
`= volume of the Sample solution (mL)
`V
`= area of the sample system (cm2)
`A
`Acceptance criteria: NMT 10.0 mg/cm 2
`ADDITIONAL REQUIREMENTS
`• PACKAGING AND STORAGE: Preserve in sealed, single-dose con-
`tainers at a temperature not exceeding 30(cid:176).
`
`Change to read:
`• LABELING: The label states the total amount of clonidine in
`the Transdermal System and the release rate, in mg/day, for the
`duration of the application of one system. •When more than
`one Drug Release test is given, the labeling states the Drug Re-
`lease test used only if Test 1 is not used.•(RB 1-Jan-2011)
`• USP REFERENCE STANDARDS Æ11æ
`USP Clonidine RS
`USP Clonidine Related Compound B RS
`2-[(E)-2,6-Dichlorophenylimino]-1-(1-{2-[(E)-2,6-
`dichlorophenylimino]-imidazolidin-1-yl}-ethyl)
`imidazolidine.
`486.23
`C20H20Cl4N6
`
`ª 2010 The United States Pharmacopeial Convention All Rights Reserved.
`
`NOVARTIS EXHIBIT 2023
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 3 of 3
`
`