Lisinopril dihydrate
`
`EUROPEAN PHARMACOPOEIA 5.0
`
`Reference solution (a). Dilute 5.0 ml of the stock solution to
`100.0 ml with an 8 g/l solution of ammonia R.
`Reference solution (b). Dilute 10.0 ml of the stock solution
`to 100.0 ml with an 8 g/l solution of ammonia R.
`Reference solution (c). Dilute 15.0 ml of the stock solution
`to 100.0 ml with an 8 g/l solution of ammonia R.
`The chromatographic procedure may be carried out using:
`— a stainless steel column 0.10 m long and 4 mm in
`internal diameter packed with octadecylsilyl silica gel for
`chromatography R (5 µm),
`— as mobile phase at a flow rate of 1.5 ml/min a mixture
`of 6 volumes of glacial acetic acid R, 30 volumes of
`acetonitrile R and 64 volumes of water R,
`— as detector a spectrophotometer set at 254 nm,
`— a 10 µl loop injector.
`Inject reference solution (c). Adjust the sensitivity of the
`system so that the height of the peaks are at least 50 per
`cent of the full scale of the recorder. Inject each reference
`solution and determine the peak areas.
`Establish a calibration curve with the concentration of
`the reference solutions (g/100 ml) as the abscissa and the
`corresponding areas as the ordinate.
`Inject the test solution. Using the retention time and the
`peak area determined from the chromatograms obtained
`with the reference solutions, locate and integrate the peak
`due to glycyrrhizic acid in the chromatogram obtained with
`the test solution.
`Calculate the percentage content of glycyrrhizic acid from
`the expression:
`
`A
`
`B
`
`=
`
`=
`
`concentration of monoammonium glycyrrhizate in
`the test solution determined from the calibration
`curve, in g/100 ml,
`declared percentage content of monoammonium
`glycyrrhizate CRS,
`m
`= mass of the drug, in grams,
`822 = molecular weight of glycyrrhizic acid,
`840 = molecular weight of the monoammonium
`glycyrrhizate (without any water of
`crystallisation).
`
`STORAGE
`Store protected from light.
`
`LABELLING
`The label states whether the drug is peeled or unpeeled.
`
`01/2005:1120
`corrected
`
`LISINOPRIL DIHYDRATE
`Lisinoprilum dihydricum
`
`C21H31N3O5,2H2O
`
`Mr 441.5
`
`DEFINITION
`Lisinopril dihydrate contains not less than 98.5 per
`cent and not more than the equivalent of 101.5 per
`cent of (2S)-1-[(2S)-6-amino-2-[[(1S)-1-carboxy-3-
`phenylpropyl]amino]hexanoyl]pyrrole-2-carboxylic acid,
`calculated with reference to the anhydrous substance.
`
`CHARACTERS
`A white or almost white, crystalline powder, soluble in
`water, sparingly soluble in methanol, practically insoluble in
`acetone and in ethanol.
`
`IDENTIFICATION
`Examine by infrared absorption spectrophotometry (2.2.24),
`comparing with the spectrum obtained with lisinopril
`dihydrate CRS. Examine the substances prepared as discs.
`
`TESTS
`Specific optical rotation (2.2.7). Dissolve 0.5 g in zinc
`acetate solution R and dilute to 50.0 ml with the same
`solvent. The specific optical rotation is −43 to −47,
`calculated with reference to the anhydrous substance.
`Related substances. Examine by liquid chromatography
`(2.2.29).
`Test solution. Dissolve 20.0 mg of the substance to be
`examined in mobile phase A and dilute to 10.0 ml with the
`same mobile phase.
`Reference solution (a). Dissolve the contents of 1 vial of
`lisinopril dihydrate for performance test CRS with 1.0 ml of
`mobile phase A.
`Reference solution (b). Dilute 0.5 ml of the test solution to
`50.0 ml with mobile phase A.
`The chromatographic procedure may be carried out using:
`— a stainless steel column 0.25 m long and 4.6 mm in
`internal diameter packed with octylsilyl silica gel for
`chromatography R,
`— as mobile phase at a flow rate of 1.8 ml/min:
`Mobile phase A. Prepare a mixture of 30 volumes of
`acetonitrile R and 970 volumes of a 3.12 g/l sodium
`dihydrogen phosphate R solution adjusted to pH 5.0 with
`a 50 g/l solution of sodium hydroxide R,
`Mobile phase B. Prepare a mixture of 200 ml of
`acetonitrile R and 800 ml of a 3.12 g/l sodium
`dihydrogen phosphate R solution adjusted to pH 5.0 with
`a 50 g/l solution of sodium hydroxide R,
`Time
`Mobile phase A
`Mobile phase B
`(min)
`(per cent V/V)
`(per cent V/V)
`0 → 30
`100→ 70
`0 - 35
`
`linear gradient
`
`Comment
`
`35 - 45
`
`45 - 50
`
`70
`70 → 100
`
`50 = 0
`
`100
`
`30
`30 → 0
`
`0
`
`isocratic
`
`switch to initial eluent
`composition
`restart gradient
`
`— as detector a spectrophotometer set at 210 nm,
`maintaining the temperature of the column at 50 °C.
`Equilibrate the column with mobile phase A for at least
`30 min. Adjust the sensitivity of the system so that the
`height of the principal peak in the chromatogram obtained
`with 20 µl of reference solution (b) is at least 50 per cent of
`the full scale of the recorder.
`Inject 20 µl of reference solution (a). The resulting
`chromatogram resembles that of the specimen
`chromatogram supplied with lisinopril dihydrate for
`performance test CRS in that the peaks due to impurity A
`and impurity E fall on either side of the peak due to lisinopril.
`Measure the heights A1 and A2 above the baseline of the
`
`1922
`
`See the information section on general monographs (cover pages)
`
`Flat Line Capital Exhibit 1015
`Page 1
`
`KVK-Tech, Flat Line Capital Exhibit 1015
`Page 1
`
`
`
`EUROPEAN PHARMACOPOEIA 5.0
`
`Reference solution (a). Dilute 5.0 ml of the stock solution to
`100.0 ml with an 8 g/l solution of ammonia R.
`Reference solution (b). Dilute 10.0 ml of the stock solution
`to 100.0 ml with an 8 g/l solution of ammonia R.
`Reference solution (c). Dilute 15.0 ml of the stock solution
`to 100.0 ml with an 8 g/l solution of ammonia R.
`The chromatographic procedure may be carried out using:
`— a stainless steel column 0.10 m long and 4 mm in
`internal diameter packed with octadecylsilyl silica gel for
`chromatography R (5 µm),
`— as mobile phase at a flow rate of 1.5 ml/min a mixture
`of 6 volumes of glacial acetic acid R, 30 volumes of
`acetonitrile R and 64 volumes of water R,
`— as detector a spectrophotometer set at 254 nm,
`— a 10 µl loop injector.
`Inject reference solution (c). Adjust the sensitivity of the
`system so that the height of the peaks are at least 50 per
`cent of the full scale of the recorder. Inject each reference
`solution and determine the peak areas.
`Establish a calibration curve with the concentration of
`the reference solutions (g/100 ml) as the abscissa and the
`corresponding areas as the ordinate.
`Inject the test solution. Using the retention time and the
`peak area determined from the chromatograms obtained
`with the reference solutions, locate and integrate the peak
`due to glycyrrhizic acid in the chromatogram obtained with
`the test solution.
`Calculate the percentage content of glycyrrhizic acid from
`the expression:
`
`A
`
`B
`
`=
`
`=
`
`concentration of monoammonium glycyrrhizate in
`the test solution determined from the calibration
`curve, in g/100 ml,
`declared percentage content of monoammonium
`glycyrrhizate CRS,
`m
`= mass of the drug, in grams,
`822 = molecular weight of glycyrrhizic acid,
`840 = molecular weight of the monoammonium
`glycyrrhizate (without any water of
`crystallisation).
`
`STORAGE
`Store protected from light.
`
`LABELLING
`The label states whether the drug is peeled or unpeeled.
`
`01/2005:1120
`corrected
`
`LISINOPRIL DIHYDRATE
`Lisinoprilum dihydricum
`
`C21H31N3O5,2H2O
`
`Mr 441.5
`
`DEFINITION
`Lisinopril dihydrate contains not less than 98.5 per
`cent and not more than the equivalent of 101.5 per
`cent of (2S)-1-[(2S)-6-amino-2-[[(1S)-1-carboxy-3-
`phenylpropyl]amino]hexanoyl]pyrrole-2-carboxylic acid,
`calculated with reference to the anhydrous substance.
`
`CHARACTERS
`A white or almost white, crystalline powder, soluble in
`water, sparingly soluble in methanol, practically insoluble in
`acetone and in ethanol.
`
`IDENTIFICATION
`Examine by infrared absorption spectrophotometry (2.2.24),
`comparing with the spectrum obtained with lisinopril
`dihydrate CRS. Examine the substances prepared as discs.
`
`TESTS
`Specific optical rotation (2.2.7). Dissolve 0.5 g in zinc
`acetate solution R and dilute to 50.0 ml with the same
`solvent. The specific optical rotation is −43 to −47,
`calculated with reference to the anhydrous substance.
`Related substances. Examine by liquid chromatography
`(2.2.29).
`Test solution. Dissolve 20.0 mg of the substance to be
`examined in mobile phase A and dilute to 10.0 ml with the
`same mobile phase.
`Reference solution (a). Dissolve the contents of 1 vial of
`lisinopril dihydrate for performance test CRS with 1.0 ml of
`mobile phase A.
`Reference solution (b). Dilute 0.5 ml of the test solution to
`50.0 ml with mobile phase A.
`The chromatographic procedure may be carried out using:
`— a stainless steel column 0.25 m long and 4.6 mm in
`internal diameter packed with octylsilyl silica gel for
`chromatography R,
`— as mobile phase at a flow rate of 1.8 ml/min:
`Mobile phase A. Prepare a mixture of 30 volumes of
`acetonitrile R and 970 volumes of a 3.12 g/l sodium
`dihydrogen phosphate R solution adjusted to pH 5.0 with
`a 50 g/l solution of sodium hydroxide R,
`Mobile phase B. Prepare a mixture of 200 ml of
`acetonitrile R and 800 ml of a 3.12 g/l sodium
`dihydrogen phosphate R solution adjusted to pH 5.0 with
`a 50 g/l solution of sodium hydroxide R,
`Time
`Mobile phase A
`Mobile phase B
`(min)
`(per cent V/V)
`(per cent V/V)
`0 → 30
`100→ 70
`0 - 35
`
`linear gradient
`
`Comment
`
`35 - 45
`
`45 - 50
`
`70
`70 → 100
`
`50 = 0
`
`100
`
`30
`30 → 0
`
`0
`
`isocratic
`
`switch to initial eluent
`composition
`restart gradient
`
`— as detector a spectrophotometer set at 210 nm,
`maintaining the temperature of the column at 50 °C.
`Equilibrate the column with mobile phase A for at least
`30 min. Adjust the sensitivity of the system so that the
`height of the principal peak in the chromatogram obtained
`with 20 µl of reference solution (b) is at least 50 per cent of
`the full scale of the recorder.
`Inject 20 µl of reference solution (a). The resulting
`chromatogram resembles that of the specimen
`chromatogram supplied with lisinopril dihydrate for
`performance test CRS in that the peaks due to impurity A
`and impurity E fall on either side of the peak due to lisinopril.
`Measure the heights A1 and A2 above the baseline of the
`
`1922
`
`See the information section on general monographs (cover pages)
`
`Flat Line Capital Exhibit 1015
`Page 1
`
`KVK-Tech, Flat Line Capital Exhibit 1015
`Page 1
`
`
`
`EUROPEAN PHARMACOPOEIA 5.0
`
`Lithium carbonate
`
`peaks due to impurity A and impurity E and the heights B1
`and B2 above the baseline of the lowest points of the curve
`separating these peaks from the peak due to lisinopril. The
`test is not valid unless A1 is greater than nine times B1 and
`A2 is greater than nine times B2.
`If necessary, adjust the pH of the mobile phase to 4.5 with
`phosphoric acid R and repeat the chromatography. A further
`adjustment to pH 4.0 may be necessary with some columns
`before satisfactory separation of impurity A, lisinopril and
`impurity E is obtained. If, after adjustment, the retention
`time of the peak due to impurities C and D becomes extended
`to the point where integration becomes difficult, increase the
`content of mobile phase B from 30 per cent to 40 per cent
`over the interval from 35 min to 45 min from the start of the
`chromatogram. Maintain this concentration for a further
`10 min. Return the concentration of mobile phase A to
`100 per cent over the next 10 min prior to the next injection.
`Inject 20 µl of the test solution and 20 µl of reference
`solution (b). In the chromatogram obtained with the test
`solution: the area of any peak due to impurity E is not
`greater than 0.3 times the area of the principal peak in the
`chromatogram obtained with reference solution (b) (0.3 per
`cent); the area of any peak, apart from the principal peak
`and any peak due to impurity E, is not greater than 0.3 times
`the area of the principal peak in the chromatogram obtained
`with reference solution (b) (0.3 per cent) and the sum of
`the areas of all such peaks is not greater than half the area
`of the principal peak in the chromatogram obtained with
`reference solution (b) (0.5 per cent). Disregard any peak due
`to the solvent, any peak occurring in the first 3 minutes and
`any peak with an area less than 0.05 times the area of the
`principal peak in the chromatogram obtained with reference
`solution (b).
`Water (2.5.12): 8.0 to 9.5 per cent, determined on 0.200 g
`by the semi-micro determination of water.
`Sulphated ash (2.4.14). Not more than 0.1 per cent,
`determined on 1.0 g.
`
`ASSAY
`Dissolve 0.350 g in 50 ml of distilled water R. Titrate
`with 0.1 M sodium hydroxide, determining the end-point
`potentiometrically (2.2.20).
`1 ml of 0.1 M sodium hydroxide is equivalent to 40.55 mg
`of C21H31N3O5.
`
`IMPURITIES
`
`A. (2RS)-2-amino-4-phenylbutanoic acid,
`
`B. 4-methylbenzenesulphonic acid,
`
`C. (2S)-2-[(3S,8aS)-3-(4-aminobutyl)-1,4-dioxohexahydro-
`pyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-phenylbutanoic acid
`(S,S,S-diketopiperazine),
`
`D. (2S)-2-[(3S,8aR)-3-(4-aminobutyl)-1,4-dioxohexahydro-
`pyrrolo[1,2-a]pyrazin-2(1H)-yl]-4-phenylbutanoic acid
`(R,S,S-diketopiperazine),
`
`E. (2S)-1-[(2S)-6-amino-2-[[(1R)-1-carboxy-3-
`phenylpropyl]amino]hexanoyl]pyrrole-2-carboxylic acid
`(lisinopril R,S,S-isomer),
`
`F. (2S)-1-[(2S)-6-amino-2-[[(1S)-1-carboxy-3-
`cyclohexylpropyl]amino]hexanoyl]pyrrole-2-carboxylic
`acid (cyclohexyl analogue).
`
`01/2005:0228
`
`LITHIUM CARBONATE
`
`Lithii carbonas
`
`Mr 73.9
`
`Li2CO3
`DEFINITION
`Lithium carbonate contains not less than 98.5 per cent and
`not more than the equivalent of 100.5 per cent of Li2CO3.
`CHARACTERS
`A white powder, slightly soluble in water, practically
`insoluble in alcohol.
`
`IDENTIFICATION
`A. When moistened with hydrochloric acid R, it gives a red
`colour to a non-luminous flame.
`
`General Notices (1) apply to all monographs and other texts
`
`1923
`
`Flat Line Capital Exhibit 1015
`Page 2
`
`KVK-Tech, Flat Line Capital Exhibit 1015
`Page 2
`
`
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
