l11111111mu11111111111
`
`l
`
`$71111].
`
`‘1'"[95'1/[7211371712119711121117177157' jig/@7172"ii/@1111
`
`
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1017 - Page 1
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1017 - Page 1
`
`

`

`JP XIII
`
`THE JAPANESE PHARMACOPOEIA
`THIRTEENTH EDITION
`
`Under the supervision of the Research and Development Division,
`Pharmaceutical Affairs Bureau, Ministry. of Health and Welfare
`
`Official from April 1, 1996
`
`PROPERTY Of
`SCHEH\NG-PLOUGH
`
`THE SOCIETY OF JAPANESE PHARMACOPOEIA
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1017 - Page 2
`
`

`

`Published 1996 by
`THE SOCIETY OF JAPANESE PHARMACOPOEIA
`
`2-12-15, Shibuya, Shibuya-ku, Tokyo, 150 JAPAN
`Tel: 81-3-3400-5634; Fax: 81-3-3400-3158
`
`Distributed by
`YAKUJI NIPPO, LTD.
`1, Kanda Izumicho, Chiyoda-ku, Tokyo, 101 JAPAN
`
`Notice: This English Version of the Japanese Pharmacopoeia, Thir(cid:173)
`teenth Edition, is published to meet the needs of the non-Japanese speak(cid:173)
`ing people. When and if any discrepancy arises between the Japanese
`original and its English translation, the former is authentic.
`
`ISBN4-8408-0389-7 C3047
`
`Printed in Japan
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1017 - Page 3
`
`

`

`The Ministry of Health and Welfare
`Notification No. 73
`
`In accordance with the provision of Article 41 of the Pharmaceutical Affairs Law
`(Law No. 145, 1960), we establish the Japanese Pharmacopoeia (hereinafter referred
`to as the "new Pharmacopoeia") as follows*, and will apply it from April 1, 1996.
`The Japanese Pharmacopoeia prescribed by the Ministry of Health and Welfare
`Notification No. 51 dated March 1991 according to the Law (hereinafter referred to
`as the "previous Pharmacopoeia") shall be abrogated on March 31, 1996. In this
`case, the drugs included in the previous Pharmacopoeia which have been approved
`before or on April 1, 1996, in accordance with the provision of Article 14 of the Law
`(inclusive of application mutatis mutandis in Article 23; the same hereinafter) [inclu(cid:173)
`sive of drugs (hereinafter referred to as "drugs not requiring approval") designated
`as those not requiring approval to manufacture or import on March 31, 1996, in ac(cid:173)
`cordance with the Ministry of Health and Welfare Notification No. 104 issued in
`March 1994 (matters related to designation of drugs not requiring approval to
`manufacture or import in accordance with Paragraph 1 of Article 14 of the Phar(cid:173)
`maceutical Affairs Law)], even though not admitted to the new Pharmacopoeia,
`shall be recognized to be included in the new Pharmacopoeia up to September 30,
`1997, and the standards for the previous Pharmacopoeia [limited to those for such
`drugs] shall be recognized to conform to those for the new Pharmacopoeia. The ti(cid:173)
`tles and/ or standards for drugs in the previous Pharmacopoeia, even though
`changed in the new Pharmacopoeia, shall be recognized as those in the new Phar(cid:173)
`macopoeia up to September 30, 1997. The drugs admitted to the new Phar(cid:173)
`macopoeia (except for those included in the previous Pharmacopoeia) which have
`been approved before or on April 1, 1996, (inclusive of those not requiring approv(cid:173)
`al) in accordance with the provision of Article 14 of the Law shall be recognized not
`to be included in the new Pharmacopoeia up to September 30, 1997.
`
`Naoto Kan
`Minister of Health and Welfare
`
`March 13, 1996
`
`*The word "follows" here indicates the contents of Part I and Part II in the Japanese Pharmacopoeia,
`Thirteenth Edition (pp. 1-1064).
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1017 - Page 4
`
`

`

`800
`
`Hydroxypropylmethylcellulose I Official Monographs for Part II
`
`JP XIII
`
`(2) To 0.1 g of Low Substituted Hydroxypropylcellulose
`add 10 mL of water, stir and produce a turbid solution. Add
`1 g of sodium hydroxide, shake until it becomes homogene(cid:173)
`ous, and use this solution as the sample solution. To 0.1 mL
`of the sample solution add 9 mL of diluted sulfuric acid (9
`in 10), shake well, heat in a water bath for exactly 3 minutes,
`immediately cool in an ice bath, add carefully 0.6 mL of nin(cid:173)
`hydrin TS, shake well, and allow to stand at 25°C: a red col(cid:173)
`or develops at first, and it changes to purple within 100
`minutes.
`(3) To 5 mL of the sample solution obtained in (2) add
`10 mL of a mixture of acetone and methanol (4:1), and
`shake: a white, flocculent precipitate is produced.
`
`pH To 1.0 g of Low Substituted Hydroxypropylcellulose
`add 100 mL of freshly boiled and cooled water, and shake:
`the pH of the solution is between 5.0 and 7.5.
`
`(1) Chloride-To 0.5 g of Low Substituted Hy(cid:173)
`Purity
`droxypropylcellulose add 30 mL of hot water, stir well, heat
`on a water bath for 10 minutes, and filter the supernatant liq(cid:173)
`uid by decantation while being hot. Wash the residue thor(cid:173)
`oughly with 50 mL of hot water, combine the washings with
`the filtrate, and add water to make 100 mL after cooling. To
`5 mL of the sample solution add 6 mL of dilute nitric acid
`and water to make 50 mL, and perform the test using this so(cid:173)
`lution as the test solution. Prepare the control solution with
`0.25 mL of 0.01 mol/L hydrochloric acid VS (not more
`than 0.335%).
`(2) Heavy metals-Proceed with 2.0 g of Low Sub(cid:173)
`stituted Hydroxypropylcellulose according to Method 2,
`and perform the test. Prepare the control solution with 2.0
`mL of Standard Lead Solution (not more than 10 ppm).
`(3) Arsenic Prepare the test solution with 1.0 g of Low
`Substituted Hydroxypropylcellulose, according to Method
`3, and perform the test using Apparatus B (not more than 2
`ppm).
`
`Loss on drying Not more than 6.0% (1 g, 105°C, 1 hour).
`
`Residue on ignition Not more than 1.0% (1 g).
`
`Assay
`(i) Apparatus-Reaction flask: A 5-mL screw-cap
`pressure-tight glass bottle, having an inverted conical bot(cid:173)
`tom inside, 20 mm in outside diameter, 50 mm in height up
`to the neck, 2 mL in capacity up to a height of about 30 mm,
`equipped with a pressure-tight septum of heat-resisting resin
`and also with an inside stopper or sealer of fluoroplastic.
`Heater: A square-shaped aluminum block 60 to 80 mm
`thick, having holes 20.6 mm in diameter and 32 mm in
`depth, capable of maintaining the inside temperature within
`± l°C.
`(ii) Procedure-Weigh accurately about 0.065 g of Low
`Substituted Hydroxypropylcellulose, previously dried, trans(cid:173)
`fer to the reaction flask, add 0.065 g of adipic acid, 2.0 mL
`of the internal standard solution and 2.0 mL of hydroiodic
`acid, stopper the flask tightly, and weigh accurately. Shake
`the flask for 30 seconds, heat at 150°C on the heater for 30
`minutes with repeated shaking at 5-minute intervals, and
`continue heating for an additional 30 minutes. Allow the
`flask to cool, and again weigh accurately. If the weight loss
`is less than 10 mg, use the upper layer of the mixture as the
`sample solution. Separately, take 0.065 g of adipic acid, 2.0
`mL of the internal standard solution and 2.0 mL of
`hydroiodic acid in another reaction flask, stopper tightly,
`
`and weigh accurately. Add 15 µL of isopropyl iodide for as(cid:173)
`say, and again weigh accurately. Shake the reaction flask for
`30 seconds, and use the upper layer of the content as the
`standard solution. Perform the test as directed under the
`Gas Chromatography with 2 µL each of the sample solution
`and the standard solution according to the following condi(cid:173)
`tions, and calculate the ratios, QT and Qs, of the peak area
`of isopropyl iodide to that of the internal standard.
`
`Amount (%) of hydroxypropoxyl group (C3H702)
`= QT x
`x 44 17
`Ws
`amount (mg) of the sample
`·
`Qs
`W,: Amount (mg) of isopropyl iodide in the standard solu-
`tion.
`
`Internal standard solution-A solution of n-octane in a-xy(cid:173)
`lene (1 in 50).
`Operating conditions-
`Detector: A thermal conductivity detector or hydrogen
`flame-ionization detector.
`Column: A glass column about 3 mm in inside diameter
`and about 3 m in length, packed with siliceous earth for gas
`chromatography, 180 to 250 µmin particle diameter, coated
`with methyl silicone polymer for gas chromatography at the
`ratio of 20%.
`Column temperature: A constant temperature of about
`100°c.
`Carrier gas: Helium (for thermal-conductivity detector);
`helium or nitrogen (for hydrogen flame-ionization detector).
`Flow rate: Adjust the flow rate so that the retention time
`of the internal standard is about 10 minutes.
`Selection of column: Proceed with 2 µL of the standard
`solution according to the above operating conditions. Use a
`column giving well-resolved peaks of isopropyl iodide and
`the internal standard in this order.
`
`Containers and storage Containers-Tight containers.
`
`Hydroxypropylmethylcellulose
`2208
`
`Hydroxypropylmethylcellulose 2208 is a methyl and
`hydroxypropyl mixed ether of cellulose.
`When dried, it contains not less than 19.0% and not
`more than 24.0% of methoxyl group (-OCH3: 31.03),
`and not less than 4.0% and not more than 12.0% of
`hydroxypropoxyl group (-OC3H60H: 75.09).
`The kinematic viscosity of Hydroxypropylmethyl(cid:173)
`cellulose 2208 is shown in square millimeter second
`(mm2/ s) on the label.
`Description Hydroxypropylmethylcellulose 2208 occurs as
`white to yellowish white, powder or granules. It is odorless
`or has a slight, characteristic odor. It is tasteless.
`It is practically insoluble in hot water, in dehydrated
`ethanol, in acetone and in ether.
`It swells with water and becomes a clear or slightly turbid,
`viscous solution.
`
`Identification
`(1) To 1 g of Hydroxypropylmethylcel(cid:173)
`lulose 2208 add 100 mL of hot water, cool to room tempera(cid:173)
`ture with stirring, and use this as the sample solution. Add
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1017 - Page 5
`
`

`

`JP XIII
`
`Official Monographs for Part II I Hydroxypropylmethylcellulose
`
`801
`
`anthrone TS gently to 5 mL of the sample solution: a blue to
`blue-green color is produced at the zone of contact.
`(2) To 0.1 mL of the sample solution obtained in (l) add
`9 mL of diluted sulfuric acid (9 in 10), shake, heat in a water
`bath for exactly 3 minutes, immediately cool in an ice bath,
`add carefully 0.6 mL of ninhydrin TS, shake, and allow to
`stand at 25°C: a red color develops at first, and it changes to
`purple within 100 minutes.
`(3) Take 5 mg of Hydroxypropylcellulose 2208 in a
`small test tube, add 2 drops of a solution of 25% hydrated
`benzoyl peroxide in acetone (1 in 10), evaporate on a water
`bath to dryness, fix a glass rod, which is moistened with
`chromotropic acid TS at the lower end, in the small test tube
`with a cork stopper, and heat in a bath at 125°C for 5 to 6
`minutes: a red-purple color develops in the chromotropic
`acid TS.
`(4) Heat the sample solution obtained in (1) in a water
`bath: a white turbidity or precipitate is produced, which dis(cid:173)
`appears upon cooling the solution.
`
`Viscosity Weigh exactly Hydroxypropylmethylcellulose
`2208, equivalent to 2.000 g of solid, calculated on the dried
`basis, add 98 mL of water previously heated to 85°C, and
`stir by mechanical means for 10 minutes. Continue the stir(cid:173)
`ring for another 40 minutes in an ice bath until the solution
`is complete, add water to make 100.0 g, and centrifuge the
`solution if necessary, to expel any entrapped air. Determine
`the viscosity according to Method 1 under the Viscosity De(cid:173)
`termination at 20°C. The viscosity of Hydroxypropylmethyl(cid:173)
`cellulose 2208 is not less than 80% and not more than 120%
`of that stated on the label.
`
`pH To 1.0 g of Hydroxypropylmethylcellulose 2208 add
`100 mL of hot water, shake to form a suspension, and cool
`to room temperature: the pH of the solution thus obtained
`is between 5.0 and 8.0.
`
`Purity
`(1) Clarity and color of solution-To 0.5 g of Hy(cid:173)
`droxypropylmethylcellulose 2208 add 20 mL of hot water,
`and stir well to disperse by heating on a water bath. Cool to
`5°C, add water to make 50 mL, transfer to a Nessler tube,
`and observe transversely the turbidity of the solution: the
`turbidity of the solution is not more intense than the follow(cid:173)
`ing control solution.
`Control solution: To 2.0 mL of 0.005 mol/ L sulfuric acid
`VS add 1 mL of dilute hydrochloric acid, 45 mL of water
`and 2 mL of barium chloride TS, mix, allow to stand for 10
`minutes, and shake before use.
`(2) Chloride-To 1.0 g of Hydroxypropylmethylcellu(cid:173)
`lose 2208 add 30 mL of hot water, stir well, heat on a water
`bath for 10 minutes, filter while hot, wash the residue well
`with hot water, combine the washings with the filtrate, and
`add water to make 100 mL after cooling. To 5 mL of the so(cid:173)
`lution add 6 mL of dilute nitric acid and water to make 50
`mL, and perform the test using this solution as the test solu(cid:173)
`tion. Prepare the control solution with 0.40 mL of 0.01
`mol/L hydrochloric acid VS (not more than 0.284%).
`(3) Heavy metals-Proceed with 2.0 g of Hydroxypro(cid:173)
`pylmethylcellulose 2208 according to Method 2, and per(cid:173)
`form the test. Prepare the control solution with 2.0 mL of
`Standard Lead Solution (not more than 10 ppm).
`(4)
`Iron-Prepare the test solution with 0.20 g of Hydro(cid:173)
`xypropylmethylcellulose 2208 according to Method 3, and
`perform the tast according to Method A. Prepare the con-
`
`trol solution with 2.0 mL of Standard Iron Solution (not
`more tha 100 ppm).
`(5) Arsenic-Prepare the test solution with 1.0 g of Hy(cid:173)
`droxypropylmethylcellulose 2208 according to Method 3,
`and perform the test using apparatus B (not more than 2
`ppm).
`
`Loss on drying Not more than 5.0% (l.O g, l05°C, 1 hour).
`
`Residue on ignition Not more than l.5% (l.O g).
`
`(i) Apparatus-Reaction flask: A 5-mL screw-cap
`Assay
`pressure-tight glass bottle, having an inverted conical bot(cid:173)
`tom inside, 20 mm in outside diameter, 50 mm in height up
`the neck, 2 mL in capacity up to a height of about 30 mm,
`equipped with a pressure-tight septum of heat-resisting resin
`and also with an inside stopper or sealer of fluoroplastic.
`Heater: A square-shaped aluminum block 60 to 80 mm
`thick, having holes 20.6 mm in diameter and 32 mm in
`depth, capable of maintaining the inside temperature within
`±1°C.
`(ii) Procedure-Weigh accurately about 0.065 g of Hy(cid:173)
`droxypropylmethylcellulose 2208, previously dried, transfer
`to the reaction flask, add 0.065 g of adipic acid, 2.0 mL of
`the internal standard solution and 2.0 mL of hydroiodic
`acid, stopper the flask tightly, and weigh accurately. Shake
`the flask for 30 seconds, heat at 150°C on the heater for 30
`minutes with repeated shaking at 5-minute intervals, and
`continue heating for an additional 30 minutes. Allow the
`flask to cool, and again weigh accurately. If the weight loss
`is less than 10 mg, use the upper layer of the mixture as the
`sample solution. Separately, take 0.065 g of adipic acid, 2.0
`mL of the internal standard solution and 2.0 mL of hydro(cid:173)
`iodic acid in another reaction flask, and weigh accurately.
`Add 15 µL of isopropyl iodide for assay, weigh accurately,
`add 45 µL of methyl iodide for assay in the same manner,
`and again weigh accurately. Shake the reaction flask for 30
`seconds, and use the upper layer of the content as the stan(cid:173)
`dard solution. Perform the test with 2 µL each of the sample
`solution and the standard solution as directed under the Gas
`Chromatography according to the following conditions,
`and calculate the ratios, QTa and QTb, of the peak area of
`methyl iodide from the sample solution to that of the inter(cid:173)
`nal standard, and Qsa and Qsb, of the peak area of methyl
`iodide and isopropyl iodide from the standard solution to
`that of the internal standard.
`
`Content(%) of methoxyl group
`= QTa X
`Wsa
`Qsa
`amount (mg) of the sample
`
`X 21 864
`·
`
`Content(%) of hydroxypropoxyl group
`= QTb x
`x 44 17
`Wsb
`Qsb
`amount (mg) of the sample
`·
`
`W8.: Amount (mg) of methyl iodide in the standard solu(cid:173)
`tion.
`Wsb: Amount (mg) of isopropyl iodide in the standard
`solution.
`
`Internal standard solution-A solution of n-octane in o(cid:173)
`xylene (1 in 25).
`Operating <:onditions-
`Detector: A thermal conductivity detector or hydrogen
`flame-ionization detector.
`Column: A glass column about 3 mm in inside diameter
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1017 - Page 6
`
`

`

`802
`
`Hydroxypropylmethylcellulose I Official Monographs for Part II
`
`JP XIII
`
`and about 3 m in length, packed with siliceous earth for gas
`chromatography, 180 to 250 µm in diameter, coated with
`methyl silicone polymer at the ratio of 20%.
`Column temperature: A constant temperature of about
`I00°C.
`Carrier gas: Helium.
`Flow rate: Adjust the flow rate so that the retention time
`of the internal standard is about IO minutes.
`Selection of the column: Proceed with 2 µL of the stan(cid:173)
`dard solution under the above operating conditions. Use a
`column giving well-resolved peaks of methyl iodide, iso(cid:173)
`propyl iodide and the internal standard in this order.
`
`Containers and storage Containers-Well-closed contain(cid:173)
`ers.
`
`Hydroxypropylmethylcellulose
`2906
`
`Hydroxypropylmethylcellulose 2906 is a methyl and
`hydroxypropyl mixed ether of cellulose.
`When dried, it contains not less than 27 .0% and not
`more than 30.0% of methoxyl group (-OCH3: 31.03),
`and not less than 4.0% and not more than 7 .5% of
`hydroxypropoxyl group (-OC3H60H: 75.09).
`The kinematic viscosity of Hydroxypropylmethyl(cid:173)
`cellulose 2906 is shown in square millimeter second
`(mm2/ s) on the label.
`
`Description Hydroxypropylmethylcellulose 2906 occurs as
`white to yellowish white, powder or granules. It is odorless
`or has a slight, characteristic odor. It is tasteless.
`It is practically insoluble in dehydrated ethanol and in
`ether.
`It swells with water and becomes a clear or slightly turbid,
`viscous solution.
`
`Identification
`(1) To 1 g of Hydroxypropylmethylcellu(cid:173)
`lose 2906 add IOO mL of hot water, cool to room tempera(cid:173)
`ture with stirring, and use this as the sample solution. Add
`anthrone TS gently to 5 mL of the sample solution: a blue to
`blue-green color is produced at the zone of contact.
`(2) To 0.1 mL of the sample solution obtained in (1) add
`9 mL of diluted sulfuric acid (9 in IO), shake, heat in a water
`bath for exactly 3 minutes, immediately cool in an ice bath,
`add carefully 0.6 mL of ninhydrin TS, shake, and allow to
`stand at 25°C: a red color develops at first, and it changes to
`purple within IOO minutes.
`(3) Take 5 mg of Hydroxypropylmethylcellulose 2906 in
`a small test tube, add 2 drops of a solution of 25% hydrated
`benzoyl peroxide in acetone (1 in IO), evaporate on a water
`bath to dryness, fix a glass rod, which is moistened with
`chromotropic acid TS at the lower end, into the small test
`tube with a cork stopper, and heat in a bath at 125°C for 5
`to 6 minutes: a red- purple color develops in chromotropic
`acid TS.
`(4) Heat the sample solution obtained in (1) in a water
`bath: a white turbidity or precipitate is produced, which dis(cid:173)
`appears upon cooling the solution.
`
`Viscosity Weigh exactly Hydroxypropylmethylcellulose
`
`2906, equivalent to 2.000 g of dried solid, calculated on the
`dried basis, add 98 mL of water previously heated to 85°C,
`and stir by mechanical means for IO minutes. Continue the
`stirring for another 40 minutes in an ice bath until the solu(cid:173)
`tion is complete, add water to make IOO.O g, and if necessa(cid:173)
`ry, centrifuge the solution to expel any entrapped air. Deter(cid:173)
`mine the viscosity as directed in Method 1 under the Viscosi(cid:173)
`ty at 20°C. The viscosity of Hydroxypropylmethylcellulose
`2906 is not less than 80% and not more than 120% of that
`stated on the label.
`
`pH To 1.0 g of Hydroxypropylmethylcellulose 2906 add
`100 mL of hot water, shake to form a suspension, and cool
`to room temperature: the pH of the solution thus obtained
`is between 5.0 and 8.0.
`
`Purity
`(1) Clarity and color of solution-To 0.5 g of
`Hydroxypropylmethylcellulose 2906 add 20 mL · of hot
`water, and stir well to disperse by heating on a water bath.
`Cool to 5°C, add water to make 50 mL, transfer to a Nessler
`tube, and observe transversely the turbidity of the solution:
`the solution is not more intense than the following control
`solution.
`Control solution: To 2.0 mL of 0.005 mol/L sulfuric acid
`VS add 1 mL of dilute hydrochloric acid, 45 mL of water
`and 2 mL of barium chloride TS, mix, allow to stand for IO
`minutes, and shake before use.
`(2) Chloride-To 1.0 g of Hydroxypropylmethylcellu(cid:173)
`lose 2906 add 30 mL of hot water, stir well, heat on a water
`bath for IO minutes, filter by decantation while hot, wash
`the residue well with hot water, combine the washings with
`the filtrate, and add water to make IOO mL after cooling. To
`5 mL of the solution add 6 mL of dilute nitric acid and
`water to make 50 mL, and perform the test using this solu(cid:173)
`tion as the test solution. Prepare the control solution with
`0.40 mL of 0.01 mol/L hydrochloric acid VS (not more
`than 0.284%).
`(3) Heavy metals-Proceed with 2.0 g of Hydrox(cid:173)
`ypropylmethylcellulose 2906 according to Method 2, and
`perform the test. Prepare the control solution with 2.0 mL
`of Standard Lead Solution (not more than IO ppm).
`(4)
`Iron-Prepare the test solution with 0.20 g of
`Hydroxypropylmethylcellulose 2906 according to Method 3,
`and perform the test according to Method A. Prepare the
`control solution with 2.0 mL of Standard Iron Solution (not
`more than IOO ppm).
`(5) Arsenic-Prepare the test solution with 1.0 g of
`Hydroxypropylmethylcellulose 2906 according to Method 3,
`and perform the test using apparatus B (not more than 2
`ppm).
`
`Loss on drying Not more than 5.0% (1 g, I05°C, 1 hour).
`
`Residue on ignition Not more than 1.5% (1.0 g).
`
`(i) Apparatus-Reaction flask: A 5-mL screw-cap
`Assay
`pressure-tight glass bottle, having an inverted conical bot(cid:173)
`tom inside, 20 mm in outside diameter, 50 mm in height up
`the neck, 2 mL in capacity up to a height of about 30 mm,
`equipped with a pressure-tight septum of heat-resisting resin
`and also with an inside stopper or sealer of fiuoroplastic.
`Heater: A square-shaped aluminum block 60 to 80 mm
`thick, having holes 20.6 mm in diameter and 32 mm in
`depth, capable of maintaining the inside temperature
`within ± 1 °C.
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1017 - Page 7
`
`

`

`JP XIII
`
`Official Monographs for Part II I Hydroxypropylmethylcellulose
`
`803
`
`(ii) Procedure-Weigh accurately about 0.065 g of
`Hydroxypropylmethylcellulose 2906, previously dried, trans(cid:173)
`fer to the reaction flask, add 0.065 g of adipic acid, 2.0 mL
`of the internal standard solution and 2.0 mL of hydroiodic
`acid, stopper the flask tightly, and weigh accurately. Shake
`the flask for 30 seconds, heat at 150°C on the heater for 30
`minutes with repeated shaking at 5-minute intervals, and
`continue heating for an additional 30 minutes. Allow the
`flask to cool, and again weigh accurately. If the weight loss
`is less than 10 mg, use the upper layer of the mixture as the
`sample solution. Separately, take 0.065 g of adipic acid, 2.0
`mL of the internal standard solution and 2.0 mL of
`hydroiodic acid in another reaction flask, and weigh ac(cid:173)
`curately. Add 15 µL of isopropyl iodide for assay, weigh ac(cid:173)
`curately, add 45 µL of methyl iodide for assay in the same
`manner, and again weigh accurately. Shake the reaction
`flask for 30 seconds, and use the upper layer of the content
`as the standard solution. Perform the test with 2 µL each of
`the sample solution and the standard solution as directed un(cid:173)
`der the Gas Chromatography according to the following
`conditions, and calculate the ratios, QTa and QTb, of the
`peak area of methyl iodide from the sample solution to that
`of the internal standard, and Qsa and Qsb, of the peak area
`of methyl iodide and isopropyl iodide from the standard so(cid:173)
`lution to that of the internal standard.
`
`Content (%) of methoxyl group (CH30)
`= amount (mg) of the sample
`X QTa X Wsa X 21.864
`Osa Wsb
`Content(%) of hydroxypropoxyl group (C3H702)
`= amount (mg) of the sample
`X QTb X 44.17
`Qsb
`W8.: Amount (mg) of methyl iodide in the standard solu(cid:173)
`tion.
`Wsb: Amount (mg) of isopropyl iodide in the standard so-
`lution.
`
`Internal standard solution-A solution of n-octane in o-xy(cid:173)
`lene (1 in 25).
`Operating conditions-
`Detector: A thermal conductivity detector or hydrogen
`flame-ionization detector.
`Column: A glass column about 3 mm in inside diameter
`and about 3 m in length, packed with siliceous earth for gas
`chromatography, 180 to 250 µm in diameter, coated with
`methyl silicone polymer at the ratio of 20%.
`Column temperature: A constant temperature of about
`100°c.
`Carrier gas: Helium
`Flow rate: Adjust the flow rate so that the retention time
`of the internal standard is about 10 minutes.
`Selection of the column: Proceed with 2 µL of the stan(cid:173)
`dard solution under the above operating conditions. Use a
`iodide,
`column giving well-resolved peaks of methyl
`isopropyl iodide and the internal standard in this order.
`
`Containers and storage Containers-Well-closed contain(cid:173)
`ers.
`
`Hydroxypropylmethylcellulose
`2910
`
`Hydroxypropylmethylcellulose 2910 is a methyl and
`hydroxypropyl mixed ether of cellulose. When dried,
`it contains not less than 28.0% and not more than
`30.0% of methoxyl group (-OCH3: 31.03), and not
`less than 7 .0% and not more than 12.0% of hydrox(cid:173)
`ypropoxyl group (-OC3H 60H: 75.09).
`The kinematic viscosity of Hydroxypropylmethyl(cid:173)
`cellulose 2910 is shown in square millimeter second
`(mm2/ s) on the label.
`Description Hydroxypropylmethylcellulose 2910 occurs as
`white to yellowish white, powder or granules. It is odorless
`or has a slight, characteristic odor. It is tasteless.
`It is practically insoluble in dehydrated ethanol and in
`ether.
`It swells in water and a clear or slightly turbid, viscous so(cid:173)
`lution is produced.
`
`(1) To 1 g of Hydroxypropylmethylcellu(cid:173)
`Identification
`lose 2910 add 100 mL of hot water, cool to room tempera(cid:173)
`ture with stirring, and use this as the sample solution. Add
`anthrone TS gently to 5 mL of the sample solution: a blue to
`blue-green color is produced at the zone of contact.
`(2) To 0.1 mL of the sample solution obtained in (1) add
`9 mL of diluted sulfuric acid (9 in 10), shake, heat in a water
`bath for exactly 3 minutes, immediately cool in an ice bath,
`add carefully 0.6 mL of ninhydrin TS, shake, and allow to
`stand at 25 °C: a red color develops at first, and it changes to
`purple within 100 minutes.
`(3) Take5 mg of Hydroxypropylmethylcellulose 2910 in
`a small test tube, add 2 drops of a solution of 25% hydrated
`benzoyl peroxide in acetone (1 in 10), evaporate on a water
`bath to dryness, fix a glass rod, which is moistened with
`chromotropic acid TS at the lower end, into the small test
`tube with a cork stopper, and heat in a bath at 125°C for 5
`to 6 minutes: a red-purple color develops in chromotropic
`acid TS.
`(4) Heat the sample solution obtained in (1) in a water
`bath: a white turbidity or precipitate is produced, which dis(cid:173)
`appears upon cooling the solution.
`
`Viscosity Weigh exactly Hydroxypropylmethylcellulose
`2910, equivalent to 2.000 g of dried solid, calculated on the
`dried basis, add 98 mL of water previously heated to 85 °C,
`and stir by mechanical means for 10 minutes. Continue the
`stirring for another 40 minutes in an ice bath until the solu(cid:173)
`tion is complete, add water to make 100.0 g, and if necessa(cid:173)
`ry, centrifuge the solution to expel any entrapped air. Deter(cid:173)
`mine the viscosity as directed in Method 1 under the Viscosi(cid:173)
`ty at 20°C. The viscosity of Hydroxypropylmethylcellulose
`2910 is not less than 80% and not more than 120% of that
`stated on the label.
`
`pH To 1.0 g of Hydroxypropylmethylcellulose 2910 add
`100 mL of hot water, shake to form a suspension, and cool
`to room temperature: the pH of the solution thus obtained
`is between 5.0 and 8.0.
`
`(1) Clarity and color of solution-To 0.5 g of
`Purity
`Hydroxypropylmethylcellulose 2910 add 20 mL of hot
`
`Petitioner Mylan Pharmaceuticals Inc. - Exhibit 1017 - Page 8
`
`

`

`804
`
`Hydroxypropyl I Official Monographs for Part II
`
`JP XIII
`
`water, and stir well to disperse by heating on a water bath.
`Cool to 5°C, add water to make 50 mL, transfer to a Nessler
`tube, and observe transversely the turbidity of the solution:
`the solution is not more intense than the following control
`solution.
`Control solution: To 2.0 mL of 0.005 mol/ L sulfuric acid
`VS add 1 mL of dilute hydrochloric acid, 45 mL of water
`and 2 mL of barium chloride TS, mix, allow to stand for 10
`minutes, and shake before use.
`(2) Chloride-To 1.0 g of Hydroxypropylmethylcellu(cid:173)
`lose 2910 add 30 mL of hot. water, stir well; heat on a water
`bath for 10 minutes, filter by decantation while hot, wash
`the residue well with hot water, combine the washings with
`the filtrate, and add water to make 100 mL after cooling. To
`5 mL of the solution add 6 mL of dilute nitric acid and
`water to make 50 mL, and perform the test using this solu(cid:173)
`tion as the test solution. Prepare the control solution with
`0.40 mL of 0.01 mol/L hydrochloric acid VS (not more
`than 0.284%).
`(3) Heavy metals-Proceed with 2.0 g of Hydrox(cid:173)
`ypropylmethylcellulose 2910 according to Method 2, and
`perform the test. Prepare the control solution with 2.0 mL
`of Standard Lead Solution (not more than 10 ppm).
`(4)
`Iron-Prepare the test solution with 0.20 g of
`Hydroxypropylmethylcellulose 2910 according to Method 3,
`and perform the test according to Method A. Prepare the
`control solution with 2.0 mL of Standard Iron Solution (not
`more than 100 ppm).
`(5) Arsenic-Prepare the test solution with 1.0 g of
`Hydroxypropylmethylcellulose 2910 according to Method 3,
`and perform the test using apparatus B (not more than 2
`ppm).
`
`Loss on drying Not more than 5.0% (1 g, l05°C, 1 hour).
`
`Residue on ignition Not more than L5% (1.0 g).
`
`(i) Apparatus-Reaction flask: A 5-mL screw-cap
`Assay
`pressure-tight glass bottle, having an inverted conical bot(cid:173)
`tom inside, 20 mm in outside diameter, 50 mm in height up
`the neck, 2 mL in capacity up to a height of about 30 mm,
`equipped with a pressure-tight septum of heat-resisting resin
`and also with an inside stopper or sealer of fluoroplastic.
`Heater: A square-shaped aluminum block 60 to 80 mm
`thick, having holes 20.6 mm in diameter and 32 mm in
`depth, capable of maintaining the inside temperature
`within ± 1 °C.
`(ii) Procedure-Weigh accurately about 0.065 g of
`Hydroxypropylmethylcellulose 2910, previously dried, trans(cid:173)
`fer to the reaction flask, add 0.065 g of adipic acid, 2.0 mL
`of the internal standard solution and 2.0 mL of hydroiodic
`acid, stopper the flask tightly, and weigh accurately. Shake
`the flask for 30 seconds, heat at 150°C on the heater for 30
`minutes with repeated shaking at 5-minute intervals, and
`continue heating for an additional 30 minutes. Allow the
`flask to cool, and again weigh accurately. If the weight loss
`is less than IO mg, use the upper layer of the mixture as the
`sample solution. Separately, take 0.065 g of adipic acid, 2.0
`mL of the internal standard solution and 2.0 mL of
`hydroiodic acid in another reaction flask, and weigh ac(cid:173)
`curately. Add 15 µL of isopropyl iodide for assay, weigh ac(cid:173)
`curately, add 45 µL of methyl iodide for assay in the same
`manner, and again weigh accurately. Shake the reaction
`flask for 30 seconds, and use the upper layer of the content
`
`as the standard solution. Perform the test with 2 µL each of
`the sample solution and the standard solution as directed un(cid:173)
`der the Gas Chromatography according to the following
`conditions, and calculate the ratios, QTa and QTu, of the
`peak area of methyl iodide from the sample solution to that
`of the internal standard, and Qsa and Qsb, of the peak area
`of methyl iodide and isopropyl iodide from the standard so(cid:173)
`lution to that of the internal standard.
`
`Content (%) of methoxyl group (CH30)
`= amount (mg) of the sample
`X QTa X Wsa X 21.864
`Qsa Wsb
`Content (%) of hydroxypropoxyl group (C3H70 2)
`= amount (mg) of the sample
`x QTb x 44.17
`Qsb
`Wsa: Amount (mg) of methyl iodide in the standard sol~­
`tion.
`Wsb: Amount (mg) of isopropyl iodide in the standard so(cid:173)
`lution.
`
`Internal standard solution-A solution of n-octane in a-xy(cid:173)
`lene (1 in