part 452—macrolide antibiotic drugs · 911 food and drug administration, hhs pt. 452 (ii) samples...

911

Food and Drug Administration, HHS Pt. 452

(ii) Samples required:(a) The mitomycin used in making

the batch: Five packages, each contain-ing approximately 100 milligrams.

(b) The batch:(1) For all tests except sterility: A

minimum of 25 immediate containers.(2) For sterility testing: 20 immediate

containers, collected at regular inter-vals throughout each filling operation.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Reconstitute as di-rected in the labeling. Using a suitablehypodermic needle and syringe, removeall of the withdrawable contents fromeach container if it is represented as asingle dose container; or if the labelingspecifies the amount of potency in agiven volume of the resultant prepara-tion, remove an accurately measuredrepresentative portion from each con-tainer. Dilute the solution thus ob-tained with sufficient 1 percent potas-sium phosphate buffer, pH 6.0 (solution1), to give a stock solution of conven-ient concentration. Further dilute thestock solution with solution 1 to thereference concentration of 1 microgramof mitomycin per milliliter (esti-mated).

(2) Sterility. Proceed as directed in§ 436.20 of this chapter, using the meth-od described in paragraph (e)(1) of thatsection.

(3) Pyrogens. Proceed as directed in§ 436.32(a) of this chapter, using a solu-tion containing 0.5 milligram ofmitomycin per milliliter.

(4) [Reserved](5) Depressor substances. Proceed as

directed in § 436.35 of this chapter.(6) Moisture. Proceed as directed in

§ 436.201 of this chapter.(7) pH. Proceed as directed in § 436.202

of this chapter using the drug reconsti-tuted as directed in the labeling.

(8) Identity. Proceed as directed in§ 436.310 of this chapter.

[39 FR 19145, May 30, 1974, as amended at 46FR 60568, Dec. 11, 1981; 50 FR 19920, May 13,1985]

PART 452—MACROLIDE ANTIBIOTICDRUGS

Subpart A—Bulk Drugs

Sec.452.10 Erythromycin.452.15 Erythromycin estolate.452.25 Erythromycin ethylsuccinate.452.25a Sterile erythromycin

ethylsuccinate.452.30a Sterile erythromycin gluceptate.452.32a Sterile erythromycin lactobionate.452.35 Erythromycin stearate.452.50 Clarithromycin.452.60 Azithromycin.452.75 Troleandomycin.

Subpart B—Oral Dosage Forms

452.110 Erythromycin oral dosage forms.452.110a Erythromycin tablets.452.110b Erythromycin enteric-coated tab-

lets.452.110c Erythromycin capsules.452.110d Erythromycin particles in tablets.452.115 Erythromycin estolate oral dosage

forms.452.115a Erythromycin estolate tablets.452.115b Erythromycin estolate capsules.452.115c Erythromycin estolate oral suspen-

sion.452.115d Erythromycin estolate for oral sus-

pension.452.115e Erythromycin estolate for pediatric

drops.452.115f Erythromycin estolate chewable

tablets.452.115g Erythromycin estolate and

sulfisoxazole acetyl oral suspension.452.125 Erythromycin ethylsuccinate oral

dosage forms.452.125a Erythromycin ethylsuccinate

chewable tablets.452.125b Erythromycin ethylsuccinate oral

suspension.452.125c Erythromycin ethylsuccinate for

oral suspension.452.125d Erythromycin ethylsuccinate tab-

lets.452.125e Erythromycin ethylsuccinate-

sulfisoxazole acetyl for oral suspension.452.135 Erythromycin stearate oral dosage

forms.452.135a Erythromycin stearate tablets.452.135b Erythromycin stearate oral suspen-

sion.452.135c Erythromycin stearate for oral sus-

pension.452.150 Clarithromycin oral dosage forms.452.150a Clarithromycin tablets.452.150b Clarithromycin granules for oral

suspension.

VerDate 09<APR>98 09:55 Apr 16, 1998 Jkt 179070 PO 00000 Frm 00905 Fmt 8010 Sfmt 8010 Y:\SGML\179070.TXT 179070-3

912

21 CFR Ch. I (4–1–98 Edition)§ 452.10

452.160 Azithromycin oral dosage forms.452.160a Azithromycin capsules.452.160b Azithromycin for oral suspension.452.175 Troleandomycin oral dosage forms.452.175a Troleandomycin capsules.452.175b Troleandomycin oral suspension.452.175c Troleandomycin for oral suspen-

sion.452.175d Troleandomycin chewable tablets.

Subpart C—Injectable Dosage Forms

452.225 Erythromycin ethylsuccinate injec-tion.

452.230 Sterile erythromycin gluceptate.452.232 Erythromycin lactobionate

injectable dosage forms.452.232a Erythromycin lactobionate for in-

jection.452.232b Sterile erythromycin lactobionate.

Subpart D—Ophthalmic Dosage Forms

452.310 Erythromycin ophthalmic ointment.

Subpart E [Reserved]

Subpart F—Dermatologic Dosage Forms

452.510 Erythromycin dermatologic dosageforms.

452.510a Erythromycin ointment.452.510b Erythromycin topical solution.452.510d Erythromycin-benzoyl peroxide

topical gel.452.510e Erythromycin topical gel.

Subpart G [Reserved]

Subpart H—Rectal Dosage Forms

452.710 Erythromycin suppositories.

Subpart I [Reserved]

Subpart J—Certain Other Dosage Forms

452.910 Erythromycin for prescriptioncompounding.

AUTHORITY: 21 U.S.C. 357.

Subpart A—Bulk Drugs

§ 452.10 Erythromycin.(a) Requirements for certification—(1)

Standards of identity, strength, quality,and purity. Erythromycin is the odor-less, white to grayish-white or slightlyyellow compound of a kind of erythro-mycin or a mixture of two or moresuch compounds. It is so purified anddried that:

(i) It contains not less than 850micrograms of erythromycin per milli-gram calculated on an anhydrous basis.

(ii) [Reserved](iii) Its moisture content is not more

than 10 percent.(iv) Its pH is not less than 8.0 or more

than 10.5.(v) Its residue on ignition is not more

than 2.0 percent.(vi) Its heavy metals content is not

more than 50 parts per million.(vii) It gives a positive identity test

for erythromycin.(viii) It is crystalline.(2) Labeling. It shall be labeled in ac-

cordance with the requirements of§ 432.5 of this chapter.

(3) Requests for certification; samples.In addition to the requirements of§ 431.1 of this chapter, each such re-quest shall contain:

(i) Results of tests and assays on thebatch for potency, moisture, residue onignition, heavy metals, pH, identity,and crystallinity.

(ii) Samples required: 10 packages,each containing not less than 500 milli-grams.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Dissolve an accu-rately weighed sample in sufficientmethyl alcohol to give a concentrationof 10 milligrams of erythromycin baseper milliliter (estimated). Dilute thissolution further with sufficient 0.1Mpotassium phosphate buffer, pH 8.0 (so-lution 3), to give a stock solution con-taining 1.0 milligram of erythromycinbase per milliliter (estimated). Furtherdilute an aliquot of the stock solutionwith solution 3 to the reference con-centration of 1.0 microgram of erythro-mycin base per milliliter (estimated).

(2) [Reserved](3) Moisture. Proceed as directed in


of this chapter, except standardize thepH meter with pH 7.0 and pH 10.0 buff-ers and prepare the sample as follows:Dissolve 200 milligrams of sample in 5milliliters of reagent grade methyl al-cohol. Add 95 milliliters of water andmix. Record the pH when an equi-librium value has been reached.

(5) Residue on ignition. Proceed as di-rected in § 436.207(a) of this chapter.

(6) Heavy metals. Proceed as directedin § 436.208 of this chapter.


913

Food and Drug Administration, HHS § 452.25

(7) Crystallinity. Proceed as directedin § 436.203(a) of this chapter.

(8) Identity test. Proceed as directedin § 436.211 of this chapter, using thesample preparation method describedin paragraph (b)(3) of that section.

[39 FR 19149, May 30, 1974, as amended at 42FR 38564, July 29, 1977; 43 FR 9801, Mar. 10,1978; 50 FR 19920, May 13, 1985]

§ 452.15 Erythromycin estolate.(a) Requirements for certification—(1)

Standards of identity, strength, quality,and purity. Erythromycin estolate isthe lauryl sulfate salt of the propionylester of a kind of erythromycin or amixture of two or more such salts. Itoccurs as a white powder. It is solublein alcohol, methyl alcohol, acetone,and chloroform, but is practically in-soluble in water. It is so purified anddried that:

(i) It contains not less than 600micrograms of erythromycin per milli-gram, calculated on an anhydrousbasis.

(ii) Its free erythromycin content isnot more than 3.0 percent.

(iii) Its moisture content is not morethan 4.0 percent.

(iv) Its pH is not less than 4.5 normore than 7.0.

(v) It gives positive identity tests forerythromycin estolate.

(vi) It is crystalline.(2) Labeling. It shall be labeled in ac-



(i) Results of tests and assays on thebatch for potency, free erythromycincontent, moisture, pH, crystallinity,and identity.

(ii) Samples of the batch: A mini-mum of 10 containers, each containingnot less than 300 milligrams.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Dissolve an accu-rately weighed sample in sufficientmethyl alcohol to give a concentrationof 1.0 milligram of erythromycin baseper milliliter (estimated). Immediatelydilute this solution further with 0.1Mpotassium phosphate buffer, pH 8.0 (so-

lution 3), to give a concentration of 0.1milligram of erythromycin per milli-liter (estimated). Hydrolyze this solu-tion in a 60° C. constant temperaturewater bath for 2 hours or at room tem-perature for 16 to 18 hours. Further di-lute with solution 3 to the referenceconcentration of 1.0 microgram oferythromycin base per milliliter (esti-mated).

(2) Free erythromycin content. Proceedas directed in § 436.362 of this chapter.

(3) Moisture. Proceed as directed in§ 436.201 of this chapter.

(4) pH. Proceed as directed in § 436.202of this chapter, using an aqueous sus-pension containing 10 milligrams permilliliter.


(6) Identity test. Proceed as directedin § 436.211 of this chapter, preparingthe sample as described in paragraph(b)(1) of that section.

[39 FR 19149, May 30, 1974, as amended at 50FR 19920, May 13, 1985; 53 FR 1920, Jan. 25,1988]

§ 452.25 Erythromycin ethylsuccinate.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycinethylsuccinate is the white, odorless,ethylsuccinate ester of erythromycin.It is so purified and dried that:



than 3.0 percent.(iv) Its pH is not less than 6.0 and not

more than 8.5.(v) Its residue on ignition is not more

than 1.0 percent.(vi) It gives a positive identity test

for erythromycin ethylsuccinate.(vii) It is crystalline.(2) Labeling. It shall be labeled in ac-

cordance with the requirements of§ 432.5(b) of this chapter.

(3) Requests for certification; samples.In addition to complying with the re-quirements of § 431.1 of this chapter,each such request shall contain:


914

21 CFR Ch. I (4–1–98 Edition)§ 452.25a

(i) Results of tests and assays on thebatch for potency, moisture, pH, resi-due on ignition, identity, and crys-tallinity.

(ii) Samples required: 10 packages,each containing approximately 500 mil-ligrams.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Dissolve an accu-rately weighed sample in sufficientmethyl alcohol to give a concentrationof 1 milligram of erythromycin baseper milliliter (estimated). Further di-lute with 0.1M potassium phosphatebuffer, pH 8.0 (solution 3), to the ref-erence concentration of 1.0 microgramof erythromycin base per milliliter (es-timated).



of this chapter, using a 1.0 percent sus-pension in water.


(6) Identity. Proceed as directed in§ 436.211 of this chapter, using the sam-ple prepared as described in paragraph(b)(3) of that section.


[39 FR 19149, May 30, 1974, as amended at 50FR 19920, May 13, 1985]

§ 452.25a Sterile erythromycinethylsuccinate.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycinethylsuccinate is the white, odorless,ethylsuccinate ester of erythromycin.It is so purified and dried that:


(ii) It is sterile.(iii) [Reserved](iv) Its moisture content is not more

than 3.0 percent.(v) Its pH is not less than 6.0 and not

more than 8.5.(vi) Its residue on ignition is not

more than 1.0 percent.(vii) It gives a positive identity test

for erythromycin ethylsuccinate.

(viii) It is crystalline.(2) Labeling. It shall be labeled in ac-



(i) Results of tests and assays on thebatch for potency, sterility, moisture,pH, residue on ignition, identity, andcrystallinity.

(ii) Samples required:(a) For all tests except sterility: 10

packages, each containing approxi-mately 500 milligrams.

(b) For sterility testing: 20 packages,each containing approximately 600 mil-ligrams.





of this chapter, using a 1.0 percent sus-pension in water.


(7) Identity. Proceed as directed in§ 436.211 of this chapter, using the sam-ple preparation method described inparagraph (b)(3) of that section.



§ 452.30a Sterile erythromycingluceptate.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin gluceptate isthe white powder of the glucoheptonic


915

Food and Drug Administration, HHS § 452.32a

acid salt of erythromycin or a mixtureof two or more such salts. It is freelysoluble in water, alcohol, and methylalcohol. It is slightly soluble in ace-tone and chloroform, but is practicallyinsoluble in ether. It is so purified anddried that:

(i) It contains not less than 600micrograms of erythromycin per milli-gram, calculated on an anhydrousbasis. If it is packaged for dispensing,its potency is satisfactory if it is notless than 90 percent and not more than115 percent of the number of milli-grams of erythromycin that it is rep-resented to contain.

(ii) It is sterile.(iii) [Reserved](iv) It is nonpyrogenic.(v) Its moisture content is not more

than 5.0 percent.(vi) Its pH in an aqueous solution

containing 25 milligrams per milliliteris not less than 6.0 nor more than 8.0.

(vii) It gives a positive identity testfor erythromycin gluceptate.

(2) [Reserved](3) Labeling. It shall be labeled in ac-



(i) Results of tests and assays on thebatch for potency, sterility, pyrogens,moisture, pH, and identity.

(ii) Samples required:(a) If the batch is packaged for re-

packing or for use as an ingredient inthe manufacture of another drug:

(1) For all tests except sterility: 10packages, each containing not lessthan 300 milligrams.

(2) For sterility testing: 20 packages,each containing approximately 300 mil-ligrams.

(b) If the batch is packaged for dis-pensing:

(1) For all tests except sterility: Aminimum of 12 immediate containersof the batch.

(2) For sterility testing: 20 immediatecontainers, collected at regular inter-vals throughout each filling operation.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: If the batch is pack-

aged for repacking or for use in manu-facturing another drug, dissolve an ac-curately weighed sample in sufficientmethyl alcohol to give a concentrationof 10 milligrams of erythromycin baseper milliliter (estimated). Dilute thissolution further with sufficient 0.1Mpotassium phosphate buffer, pH 8.0 (so-lution 3), to give a stock solution con-taining 1.0 milligram of erythromycinbase per milliliter (estimated). If it ispackaged for dispensing, reconstituteas directed in the labeling. Then usinga suitable hypodermic needle and sy-ringe, remove all of the withdrawablecontents if it is represented as a singledose container; or if the labeling speci-fies the amount of potency in a givenvolume of the resultant preparation,remove an accurately measured rep-resentative portion from each con-tainer. Dilute with solution 3 to give astock solution of convenient con-centration. Further dilute the stocksolution with solution 3 to the ref-erence concentration of 1.0 microgramof erythromycin base per milliliter (es-timated).


(3) Pyrogens. Proceed as directed in§ 436.32(b) of this chapter, using a solu-tion containing 30 milligrams of eryth-romycin per milliliter.



of this chapter, using a concentrationof 25 milligrams per milliliter.


[39 FR 19149, May 30, 1974, as amended at 46FR 16685, Mar. 13, 1981; 50 FR 19920, 19921,May 13, 1985]

§ 452.32a Sterile erythromycinlactobionate.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin lactobionateis the white to off-white powder of thelactobionate salt of erythromycin or amixture of two or more such salts. It isso purified and dried that:


916

21 CFR Ch. I (4–1–98 Edition)§ 452.32a

(i) If the erythromycin lactobionateis not packaged for dispensing, itserythromycin potency is not less than525 micrograms of erythromycin permilligram on an anhydrous basis. If theerythromycin lactobionate is packagedfor dispensing, its erythromycin po-tency is not less than 525 microgramsof erythromycin per milligram on ananhydrous basis and also, each con-tainer contains not less than 90 percentand not more than 120 percent of thenumber of milligrams of erythromycinthat it is represented to contain.

(ii) It is sterile.(iii) It is nonpyrogenic.(iv) Its moisture content is not more

than 5.0 percent.(v) Its pH is not less than 6.5 and not

more than 7.5.(vi) Its residue on ignition is not

more than 2.0 percent.(vii) Its heavy metals content is not

more than 50 parts per million.(viii) It passes the identity test.(2) Labeling. It shall be labeled in ac-



(i) Results of tests and assays on thebatch for potency, sterility, pyrogens,moisture, pH, residue on ignition,heavy metals, and identity.

(ii) Samples, if required by the Direc-tor, Center for Drug Evaluation andResearch:

(a) If the batch is packaged for re-packing or for use as an ingredient inthe manufacture of another drug:

(1) For all tests except sterility: Aminimum of 12 immediate containers.

(2) For sterility testing: 20 packages,each containing equal portions of ap-proximately 300 milligrams.

(b) If the batch is packaged for dis-pensing:

(1) For all tests except sterility: Aminimum of 12 immediate containers.


(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows:

(i) Product not packaged for dispensing(micrograms of erythromycin per milli-gram). Dissolve an accurately weighedsample with sufficient methyl alcoholto obtain a concentration of 10 milli-grams of erythromycin base per milli-liter (estimated). Further dilute an ali-quot of this solution with 0.1M potas-sium phosphate buffer, pH 8.0 (solution3), to the reference concentration of 1.0microgram of erythromycin base permilliliter (estimated).

(ii) Product packaged for dispensing.Determine both micrograms of eryth-romycin per milligram of sample andmilligrams of erythromycin per con-tainer. Use separate containers forpreparation of each sample solution asdescribed in paragraph (b)(1)(ii)(a) and(b) of this section.

(a) Micrograms of erythromycin per mil-ligram. Dissolve an accurately weighedsample with sufficient methyl alcoholto obtain a concentration of 10 milli-grams of erythromycin base per milli-liter (estimated). Further dilute an ali-quot of this solution with 0.1M potas-sium phosphate buffer, pH 8.0 (solution3), to the reference concentration of 1.0microgram of erythromycin base permilliliter (estimated).

(b) Milligrams of erythromycin per con-tainer. Reconstitute the sample as di-rected in the labeling. Then using asuitable hypodermic needle and sy-ringe, remove all of the withdrawablecontents if it is represented as a single-dose container; or, if the labeling speci-fies the amount of potency in a givenvolume of the resultant preparation,remove an accurately measured rep-resentative portion from each con-tainer. Dilute an aliquot of the solu-tion thus obtained with sterile distilledwater to obtain a concentration of 10milligrams of erythromycin base permilliliter (estimated). Further dilutean aliquot of this solution with 0.1Mpotassium phosphate buffer, pH 8.0 (so-lution 3), to the reference concentra-tion of 1.0 microgram of erythromycinbase per milliliter (estimated).



917




(5) pH. Proceed as directed in § 436.202of this chapter, using a concentrationof 50 milligrams of erythromycin permilliliter.




[51 FR 35215, Oct. 2, 1986, as amended at 55 FR11584, Mar. 29, 1990]

§ 452.35 Erythromycin stearate.(a) Requirements for certification—(1)

Standards of identity, strength, quality,and purity. Erythromycin stearate isthe odorless, white or slightly yellowpowder of the stearic acid salt of eryth-romycin. It is practically insoluble inwater but is soluble in alcohol, methylalcohol, chloroform, and ether. It is sopurified and dried that:



than 4.0 percent.(iv) Its pH is not less than 6.0 and not

more than 11.0.(v) Its residue on ignition is not more

than 1.0 percent.(vi) It gives positive identity tests for

erythromycin stearate.(vii) It is crystalline.(2) Labeling. It shall be labeled in ac-



(i) Results of tests and assays on thebatch for potency, moisture, pH residueon ignition, identity, and crystallinity.

(ii) Samples required: A minimum of10 containers, each consisting of 500milligrams.




of this chapter, using a 1 percent slurryof erythromycin stearate in water.




[39 FR 19149, May 30, 1974, as amended at 50FR 19920, 19921, May 13, 1985]

§ 452.50 Clarithromycin.(a) Requirements for certification—(1)

Standards of identity, strength, quality,and purity. Clarithromycin is 6-O-methylerythromycin A. It is so puri-fied and dried that:

(i) Its potency is not less than 960micrograms of clarithromycin activityper milligram, on an anhydrous basis.

(ii) Its moisture content is not morethan 2.0 percent.

(iii) The pH of a 0.2 percent (weightper volume) slurry in aqueous meth-anol (95:5) is not less than 7.5 and notmore than 10.0.

(iv) Its residue on ignition is notmore than 0.3 percent.

(v) Its heavy metals content is notmore than 20 parts per million.

(vi) Its specific rotation in chloro-form containing 10 milligrams ofclarithromycin per milliliter at 20 °C isbetween -89° and -95°, calculated on ananhydrous basis.

(vii) It gives a positive identity test.(viii) It is crystalline.(2) Labeling. It shall be labeled in ac-



918

21 CFR Ch. I (4–1–98 Edition)§ 452.50


(i) Results of tests and assays on thebatch for clarithromycin potency,moisture, pH, residue on ignition,heavy metals, specific rotation, iden-tity, and crystallinity.

(ii) Samples, if required by the Direc-tor, Center for Drug Evaluation andResearch: 10 packages, each containingapproximately 500 milligrams.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.216 ofthis chapter, using a constant columntemperature of 50 °C, a suitable ultra-violet detection system operating at210 nanometers, an analytical column 3to 30 centimeters long packed with areversed phase packing material suchas octadecyl hydrocarbon bonded sili-cas (3 to 10 micrometers in diameter),the inlet of this column is connected toa guard column 1 to 5 centimeters inlength packed with the same materialof 5- to 30-micrometer particle size, aconstant flow rate of 0.7 to 1.0 milli-liters per minute, and a known injec-tion volume of between 10 and 20microliters. The retention time forclarithromycin is between 5 and 6 min-utes and the retention time for 6,11-Di-O-methylerythromycin A (resolutioncompound) is between 7 and 8 minutes.Mobile phase, system suitability solu-tion, working standard and sample so-lutions, system suitability require-ments, and calculations are as follows:

(i) Mobile phase. Add 650 milliliters ofmethanol and 350 milliliters of 0.067 Mpotassium phosphate (monobasic) to asuitable container, mix well, and ad-just the pH to 4.0 with phosphoric acid.Filter through a suitable filter capableof removing particulate matter to 0.5micron in diameter. Degas the mobilephase just prior to its introductioninto the chromatograph.

(ii) Preparation of system suitability so-lution. Prepare a methanol solutioncontaining approximately 625micrograms per milliliter each ofclarithromycin and 6,11-Di-O-methylerythromycin A. Quantitativelytransfer an aliquot of this solution to asuitable volumetric flask and dilute itto volume with mobile phase to obtaina solution containing approximately

125 micrograms each of clarithromycinand 6,11-Di-O-methylerythromycin A.

(iii) Preparation of working standardsolution. Dissolve (by shaking orsonication) an accurately weighed por-tion of the clarithromycin workingstandard in sufficient methanol to ob-tain a known solution containingabout 625 micrograms ofclarithromycin activity per milliliter.Quantitatively transfer an aliquot ofthis solution to a suitable volumetricflask and dilute to volume with mobilephase and mix to obtain a known solu-tion containing approximately 125micrograms of clarithromycin activityper milliliter. Filter through a suitablefilter capable of removing particulatematter to 0.5 micron in diameter.

(iv) Sample solution. Dissolve (byshaking or sonication) an accuratelyweighed portion of the sample in suffi-cient methanol to obtain a solutioncontaining 625 micrograms ofclarithromycin activity per milliliter(estimated). Quantitatively transfer analiquot of this solution to a suitablevolumetric flask and dilute to volumewith mobile phase and mix to obtain aknown solution containing approxi-mately 125 micrograms ofclarithromycin activity per milliliter(estimated). Filter through a suitablefilter capable of removing particulatematter to 0.5 micron in diameter.

(v) System suitability requirements—(A)Asymmetry factor. The asymmetry fac-tor (AS) is satisfactory if it is not lessthan 0.9 and not more than 1.5 for theclarithromycin peak.

(B) Efficiency of the column. The abso-lute efficiency (hr) is satisfactory if itis not more than 40.0 for theclarithromycin peak.

(C) Resolution factor. The resolutionfactor (R) between the peak forclarithromycin and the peak for 6,11-Di-O-methylerythromycin A is satis-factory if it is not less than 2.0.

(D) Coefficient of variation (relativestandard deviation). The coefficient ofvariation (SR in percent of 5 replicateinjections) is satisfactory if it is notmore than 2.0 percent.

(E) Capacity factor. Calculate theclarithromycin capacity factor (k′) asfollows:


919


k′ = (tr/t0)Ø1

where:

tr = Retention time of the clarithromycinpeak; and

t0 = Void volume time.

The capacity factor is satisfactory if itis not less than 1.3 and not more than4.0. If the system suitability param-eters have been met, then proceed asdescribed in § 436.216(b) of this chapter.

(vi) Calculations. Calculate themicrograms of clarithromycin per mil-ligram of sample on an anhydrous basisas follows:

Micrograms ofclarithromycinper milligram

=× ×

× × −

A P

A C m

U S

S U

100

100( )where:

AU = Area of the clarithromycin peak (at aretention time equal to that observed forthe clarithromycin standard) in the chro-matogram of the sample;

AS = Area of the clarithromycin peak in thechromatogram of the clarithromycinworking standard;

PS = Clarithromycin activity in theclarithromycin working standard solu-tion in micrograms per milliliter;

CU = Milligrams of sample per milliliter ofsample solution; and

m = Percent moisture content of the sample.

(2) Moisture. Proceed as directed in§ 436.201 of this chapter, using the sam-ple preparation described in paragraph(d)(1) of that section and the titrationprocedure described in paragraph (e)(3)of that section, except that instead ofadding 20 milliliters of solvent A beforestarting the titration, add a sufficientvolume of solvent C to cover the elec-trodes in the dry titrating vessel.

(3) pH. Proceed as directed in § 436.202of this chapter, except standardize thepH meter with pH 7.0 and pH 10.0 buff-ers and prepare the sample as follows:Transfer 200 milligrams of the sampleto a 150-milliliter beaker. Add 5 milli-liters of methanol and then 95 milli-liters of distilled water. Place the pHelectrodes in the slurry and stir at theslowest speed possible to ensure mixingbut no vortex. After 10 minutes, whilestill stirring, determine the pH.



(6) Specific rotation. Dilute an accu-rately weighed sample with sufficientchloroform to give a concentration ofapproximately 10 milligrams ofclarithromycin per milliliter. Proceedas directed in § 436.210 of this chapter,using a 1.0-decimeter polarimeter tube,maintaining the solution at 20 °C, andcalculate the specific rotation on ananhydrous basis.

(7) Identity. Proceed as directed in§ 436.211 of this chapter, preparing thesample as follows: Prepare a 5-percentsolution of the sample in chloroformand use 0.1 millimeter matched absorp-tion cells.


[58 FR 26653, May 4, 1993]

§ 452.60 Azithromycin.(a) Requirements for certification—(1)

Standards of identity, strength, quality,and purity. Azithromycin is the dihy-drate form of(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one. It is so pu-rified and dried that:

(i) Its potency is not less than 945micrograms and not more than 1,030micrograms of azithromycin activityper milligram, on the anhydrous basis.

(ii) Its moisture content is not lessthan 4.0 percent and not more than 5.0percent.

(iii) The pH of an aqueous methanol(1:1) solution containing 2 milligramsper milliliter is not less than 9 and notmore than 11.


(v) Its heavy metals content is notmore than 25 parts per million.

(vi) The specific rotation in absoluteethanol containing 20 milligrams ofazithromycin per milliliter at 20 °C isbetween -45° to -49°, calculated on ananhydrous basis.

(vii) It is crystalline.(viii) It gives a positive identity test.(2) Labeling. It shall be labeled in ac-



920

21 CFR Ch. I (4–1–98 Edition)§ 452.60


(i) Results of tests and assays on thebatch for azithromycin potency, mois-ture, pH, residue on ignition, heavymetals, specific rotation, crystallinity,and identity.

(ii) Samples, if required by the Direc-tor, Center for Drug Evaluation andResearch: 10 packages, each containingapproximately 500 milligrams.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.216 ofthis chapter, using ambient tempera-ture, an amperometric electrochemicaldetection system with dual glassy car-bon electrodes operated in theoxidative screen mode with electrode 1set at ∂0.70 volt±0.05 volt and electrode2 at ∂0.82 volt±0.05 volt. (The ±0.05-voltvariance allows for optimization of thebackground current to 70 to 100nanoamperes.) Detection ofazithromycin occurs at electrode 2where the voltage is sufficiently highto oxidize the amine functional groupson the molecules. Use a 15-centimetersby 4.6-millimeters (inside diameter)column packed with alumina-basedpolybutadiene 5 micrometer sphericalparticles with 80-angstrom pore size(e.g., ES Industries γRP1/p). The inletof this column is connected to a guardcolumn 5 centimeters by 4.6 millime-ters (inside diameter) packed with thesame material. The flow rate is 1.5 mil-liliters per minute. Use a fixed volumeloop injector or equivalent device toinject a volume of 50 microliters intothe system. The retention time forazithromycin is between 10 and 13 min-utes. Mobile phase, working standard,sample, and resolution solutions, sys-tem suitability requirements, and cal-culations are as follows:

(i) Mobile phase. Dissolve 5.8 grams ofpotassium phosphate monobasic in2,130 milliliters of ultrapure deionizedor high-performance liquidchromatographic-grade water. Add 870milliliters of acetonitrile and mix. Themobile phase is 0.02 M potassium phos-phate monobasic: acetonitrile (71:29).Adjust the pH of the mobile phase topH 11.0±0.1 with 10 M potassium hy-droxide (about 6 milliliters). Filter themobile phase through a suitable filter

capable of removing particulate matter0.5 micron in diameter and degas it justprior to its introduction into the chro-matograph.

(ii) Preparation of working standard so-lution. Accurately weigh approximately16.5 milligrams of the azithromycinworking standard into a 100-millilitervolumetric flask. Dissolve the mate-rial, aided by brief sonication, in 10milliliters of acetonitrile and dilute tovolume with acetonitrile. Pipet 2.0 mil-liliters of this solution into a 100-milli-liter volumetric flask and dilute to vol-ume with mobile phase. This solutioncontains approximately 0.003 milligramper milliliter of azithromycin.

(iii) Sample solution. Accuratelyweigh approximately 16.5 milligrams ofsample into a 100-milliliter volumetricflask. Dissolve the sample, aided bybrief sonication, in 10 milliliters of ace-tonitrile and dilute to volume withacetonitrile. Pipet 2.0 milliliters of thissolution into a 100-milliliter volu-metric flask and dilute to volume withmobile phase.

(iv) Resolution test solution. Weigh ap-proximately 16.5 milligrams each ofazithromycin working standard andazaerythromycin A reference standardinto a 100-milliliter volumetric flask.Dissolve the materials aided by briefsonication in 10 milliliters of acetoni-trile and dilute to volume with aceto-nitrile. Pipet 2.0 milliliters of this so-lution into a 100-milliliter volumetricflask and dilute to volume with mobilephase.

(v) System suitability requirements.Using the resolution test solution, de-termine the:

(A) Asymmetry factor. The asymmetryfactor (AS) is satisfactory if it is notless than 0.9 and not more than 1.5 forthe azithromycin peak.

(B) Efficiency of the column. The abso-lute efficiency (hr) is satisfactory if itis not more than 40.0 for theazithromycin peak.

(C) Resolution factor. The resolutionfactor (R) between the peak fromazithromycin and the peak forazaerythromycin A is satisfactory if itis not less than 2.5.

(D) Coefficient of variation (relativestandard deviation). The coefficient ofvariation (SR in percent of 5 replicateinjections) is satisfactory if it is not


921


more than 2.0 percent. If the systemsuitability parameters have been met,then proceed as described in § 436.216(b)of this chapter.

(vi) Calculations. Calculate themicrograms of azithromycin per milli-gram of sample on an anhydrous basisas follows:

Micrograms ofazithromycinper milligram

=× ×

× × −

A P

A C m

U S

S U

100

100( )where:AU = Area of the azithromcin peak (at a re-

tention time equal to that observed forthe azithromycin standard) in the chro-matogram of the sample;

AS = Area of the azithromcin peak in thechromatogram of the azithromycinworking standard;

PSAzithromycin activity in the azithromycinworking standard solution inmicrograms per milliliter;

CU = Milligrams of sample per milliliter ofsample solution; and

m = Percent moisture content of the sample.


(3) pH. Proceed as directed in § 436.202of this chapter, using an aqueous meth-anol (1:1) solution containing 2 milli-grams per milliliter, prepared by dilut-ing a methanol solution containing 4milligrams of azithromycin dihydrate1:1 with distilled water.

(4) Residue on ignition. Proceed as di-rected in § 436.207(b) of this chapter, ex-cept use a temperature of 800 °C insteadof a temperature range of 500 to 600 °C.


(6) Specific rotation. Dissolve an accu-rately weighed sample with sufficientabsolute ethanol to give a concentra-tion of approximately 20 milligramsper milliliter. Proceed as directed in§ 436.210 of this chapter, except diluteand maintain the test solution at 20 °Cinstead of 25 °C. Use a 1.0-decimeter po-larimeter tube and calculate the spe-cific rotation on an anhydrous basis.


(8) Identity. Proceed as directed in§ 436.211 of this chapter, using a 0.5 per-cent potassium bromide disc preparedas described in paragraph (b)(1) of thatsection.

[58 FR 26657, May 4, 1993]

§ 452.75 Troleandomycin.(a) Requirements for certification—(1)

Standards of identity, strength, quality,and purity. Troleandomycin is thetriacetyl ester of oleandomycin base ora mixture of two or more such esters.It is a white powder. It is so purifiedthat:

(i) Its potency is not less than 750micrograms of troleandomycin per mil-ligram.

(ii) [Reserved](iii) Its loss on drying is not more

than 1.0 percent.(iv) Its pH in an aqueous alcohol so-

lution containing 100 milligrams oftroleandomycin per milliliter is notless than 7.0 and not more than 8.5.

(v) Its residue on ignition is not morethan 0.1 percent.

(vi) It gives a positive identity testfor oleandomycin.

(vii) Its Rf value by paper chroma-tography is approximately 0.85. If morethan one spot appears on the paperchromatogram, determine its acetylvalue, which is not less than 15.3 per-cent and not more than 16.0 percent.

(viii) It is crystalline.(2) Labeling. It shall be labeled in ac-



(i) Results of tests and assays on thebatch for potency, loss on drying, pH,residue on ignition, identity, Rf value,acetyl value (only if more than onespot is present in the determination ofRf value), and crystallinity.

(ii) Samples of the batch: 10 pack-ages, nine containing approximatelyequal portions of not less than 500 mil-ligrams, and one containing not lessthan 2.0 grams.

(b) Tests and methods of assay—(1) Po-tency. Use either of the following meth-ods; however, the results obtained fromthe microbiological turbidimetricassay shall be conclusive.

(i) Chemical method—(a) Reagents andequipment. (1) Methyl orange reagent:Shake 0.5M boric acid solution for 12hours (to ensure saturation) with anexcess of methyl orange indicator. Analternative method is to heat the mix-ture to about 50° C. and shake for about


922

21 CFR Ch. I (4–1–98 Edition)§ 452.75

an hour. Then allow to cool. Filter thesaturated dye solution and wash threetimes with chloroform. Store the dyesolution over chloroform.

(2) Acid-alcohol solution: Add 2 milli-liters of concentrated sulfuric acid to98 milliliters of absolute methyl alco-hol.

(3) Glycerin: Reagent grade.(4) Chloroform.(5) Glacial acetic acid.(6) Centrifuge tubes: 40 milliliters,

glass-stoppered.(b) Procedure. Using the

troleandomycin working standardwhich has been dried for 3 hours at 60°C. and a pressure of 5 millimeters orless, prepare a standard solution inchloroform containing 50.0 milligramsof oleandomycin base in 200 milliliters.Transfer 10.0 milliliters of the solutionto a 100-milliliter volumetric flask anddilute to volume with chloroform.Transfer 2.0, 4.0, 6.0, and 8.0 millilitersof this solution to glass-stoppered cen-trifuge tubes (40-milliliter size) and di-lute to a total volume of 20.0 milliliterseach with chloroform. To the 20 milli-liters of the solution present in each40-milliliter size centrifuge tube, add0.2 milliliter of glacial acetic acid, 0.2milliliter of glycerin, and 0.4 milliliterof methyl orange reagent. Shake for 5minutes and centrifuge for 3 minutes.Immediately transfer to another tube a10.0-milliliter aliquot from the chloro-form (lower) layer. Care must be exer-cised to see that no portion of the dye-glycerin phase is included with thechloroform aliquot. Add 1.0 milliliterof acid-alcohol solution to this chloro-form aliquot, mix well, and read theabsorbancy at 535 nanometers, using a1-centimeter cell and a suitable pho-tometer and using chloroform, simi-larly treated, as a blank. Prepare astandard curve, plotting the absorb-ance values of the standard solutionagainst the concentration expressed inmicrograms of oleandomycin base peraliquot. Accurately weigh the sampleto be tested to give 50 milligrams (esti-mated) of oleandomycin base. Dissolvein chloroform and make to 200 milli-liters with chloroform. Transfer 10.0milliliters to a 100-milliliter volu-metric flask and make to volume withchloroform. Transfer 5.0 milliliters to aglass-stoppered centrifuge tube and

proceed as above. Determine the po-tency of the sample from the standardcurve.

(ii) Microbiological turbidimetric assay.Proceed as directed in § 436.106 of thischapter, preparing the sample for assayas follows: Dissolve an accuratelyweighed sample in sufficient 80 percentisopropyl alcohol solution (solution 15)to obtain a stock solution containing1,000 micrograms per milliliter. Fur-ther dilute an aliquot of the stock solu-tion with distilled water to the ref-erence concentration of 25 microgramsof troleandomycin per milliliter (esti-mated).

(2) [Reserved](3) Loss on drying. Proceed as directed

in § 436.200(b) of this chapter.(4) pH. Proceed as directed in § 436.202

of this chapter, using a saturated solu-tion prepared by adding 100 milligramsof troleandomycin per milliliter ofwater-ethyl alcohol (1:1) diluent.

(5) Residue on ignition. Proceed as di-rected in § 436.207(a) of this chapter, ex-cept use a silica crucible.

(6) Identity. Dissolve about 10 milli-grams in 5 milliliters of hydrochloricacid and heat the solution in a boilingwater bath; a greenish yellow color isproduced.

(7) Rf value—(i) Apparatus and re-agents. (a) Chromatographic chamber(cylinder, glass-stoppered museum jar,11.5 inches x 3.5 inches).

(b) Chromatographic paper (8 inches x8 inches, Whatman No. 1).

(c) 0.1N hydrochloric acid.(d) Resolving solvent: Butyl acetate,

benzene, nitromethane, pyridine (5:5:5:1by volume).

(e) Spray developing reagent: Place1.0 milliliter of 10 percent platinicchloride solution and 25.0 milliliters of4 percent potassium iodide solution ina 250-milliliter volumetric flask. Fill tomark with distilled water and mixwell.

(ii) Procedure. Dissolve the sample inchloroform to give a solution contain-ing 10 to 20 milligrams ofoleandomycin base equivalent per mil-liliter. Prepare a sheet ofchromatographic paper by drawing aline of origin parallel to and 1 inchfrom the edge of the paper. Wet thepaper thoroughly with the 0.1N hydro-chloric acid and blot it firmly between


923


sheets of absorbent paper. Starting 2inches in from the edge and at 1-inchintervals, apply 3 to 5 microliters ofthe sample solutions to the startingline. Allow a few minutes for the paperto dry partially. While it is still damp,form a cylinder by bringing the outeredges together, allowing about 1-inchoverlap, and secure with a paper clip.Stand the paper in thechromatographic chamber, which hasbeen filled to a depth of one-half of aninch with the resolving solvent. Afterthe solvent front rises to a height of 4to 5 inches above the origin, removethe paper from the tank and hang it upto air dry. Spray the dried paper withthe developing reagent. Hang the paperin a 100° C. oven for 3 minutes. A purplespot becomes visible fortroleandomycin at an Rf value of about0.85. The approximate Rf values fordiacetyloleandomycin,monoacetyloleandomycin, andoleandomycin are, respectively, 0.72,0.27, and 0.13.

(8) Acetyl determination—(i) Apparatusand reagents. (a) One 3-necked Pyrexflask of approximately 45 milliliterscapacity, pear-shaped with T-joints,agar inlet tube, glass-stoppered funnel,glass condenser, and bubble counter.

(b) 50-milliliter Pyrex Erlenmeyerflask.

(c) 10-milliliter buret, calibrated to0.02 milliliter.

(d) Anhydrous methyl alcohol, rea-gent grade.

(e) 2N sodium hydroxide solution.(f) Sulfuric acid solution prepared by

adding 100 milliliters of concentratedH2SO4 to 200 milliliters of water.

(g) 1N barium chloride solution.(h) Phenolphthalein solution (1 per-

cent in ethyl alcohol).(i) Water-pumped nitrogen.(j) NaOH solution 0.015N.(ii) Procedure. Weigh accurately (to

0.01 milligram) approximately 30 milli-grams of the sample into the three-necked acetyl flask. Add 2.0 millilitersof methyl alcohol to dissolve the sam-ple; then add slowly, with gentle swirl-ing, 1.0 milliliter of NaOH solution.Connect the gas inlet tube with bubblecounter attached and adjust nitrogenflow to about two bubbles a second.Put glass-stoppered funnel incenterneck of acetyl flask and put

about 5 milliliters of H2O in the funnel.Add a boiling chip to the solution andattach condenser in the refluxing posi-tion with water cooling. Adjust burnerflame under acetyl flask to reflux solu-tion gently. Reflux for 30 minutes. Coolassembly slightly; then rinse down con-denser (still in reflux position) with afew milliliters of H2O. Reassemble con-denser to the distillation position andadd water through the funnel to makea total of approximately 5 milliliters ofH2O added to acetyl flask. Adjust burn-er flame so that about 5 milliliters ofH2O and methyl alcohol is distilledover in approximately 10 minutes. Dis-card this distillate. Cool acetyl flaskslightly. Acidify solution in flask byadding 1 milliliter of the sulfuric acidsolution through the funnel. Adjustburner flame and distill over approxi-mately 20 milliliters of distillate intoan Erlenmeyer flask in about 20 min-utes, adding water through the funnelas necessary. It is important to keepthe liquid volume in the acetyl flaskaround 2 to 3 milliliters in order to ob-tain a quantitative recovery of the ace-tic acid. Collect a second fraction ofdistillate, about 10 milliliters in vol-ume. As the second fraction is distill-ing, process the first fraction. Heat thefirst fraction and boil gently about 20seconds. Add a few drops of BaCl2 solu-tion to check if any sulfate was dis-tilled over. If the sulfate is present,discard and repeat the whole deter-mination. If the sulfate is absent, im-mediately titrate the solution with the0.015N NaOH solution to a faint-pinkendpoint, using one drop of phenol-phthalein solution as the indicator. Re-peat the above procedure with the sec-ond fraction. If the second fraction re-quires less than 0.10 milliliter of the0.015N NaOH solution and all the aceticacid has been distilled over, the deter-mination is completed. If greater thanthis, collect a third fraction of approxi-mately 10 milliliters and titrate this asbefore. Total volumes of NaOH usedand calculate results as follows:

(Milliliters of NaOH×N NaOH×0.043×100)/(Weight sample in grams)=Percent ace-tyl.


924

21 CFR Ch. I (4–1–98 Edition)§ 452.110


[39 FR 19149, May 30, 1974, as amended at 48FR 3960, Jan. 28, 1983; 50 FR 19920, 19921, May13, 1985]

Subpart B—Oral Dosage Forms§ 452.110 Erythromycin oral dosage

forms.

§ 452.110a Erythromycin tablets.(a) Requirements for certification—(1)

Standards of identity, strength, quality,and purity. Erythromycin tablets areerythromycin with suitable and harm-less buffer substances, diluents, bind-ers, lubricants, colorings, flavorings,and suitable preservatives. The po-tency of each tablet is 250 milligramsor 500 milligrams of erythromycin. Itspotency is satisfactory if it is not lessthan 90 percent and not more than 120percent of the number of milligrams oferythromycin that it is represented tocontain. Tablets shall disintegratewithin 1 hour. The loss on drying is notmore than 5.0 percent. The erythro-mycin used in making the batch con-forms to the standards prescribed by§ 452.10(a)(1), except heavy metals.

(2) Labeling. It shall be labeled in ac-cordance with the requirements of§ 432.5 of this chapter.


(i) Results of tests and assays on:(a) The erythromycin used in making

the batch for potency, pH, moisture,residue on ignition, crystallinity, andidentity.

(b) The batch for potency, disintegra-tion time, and loss on drying.

(ii) Samples required:(a) The erythromycin used in making

the batch: 10 packages, each containing500 milligrams.

(b) The batch: A minimum of 36 tab-lets.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Blend a representa-tive number of tablets in a high-speedglass blender for 2 to 3 minutes with200 milliliters of methyl alcohol. Add300 milliliters of 0.1M potassium phos-

phate buffer, pH 8.0 (solution 3), andblend again for 2 to 3 minutes. Furtherdilute with solution 3 to the referenceconcentration of 1.0 microgram oferythromycin base per milliliter (esti-mated).

(2) Loss on drying. Proceed as directedin § 436.200(b) of this chapter.

(3) Disintegration time. Proceed as di-rected in § 436.212 of this chapter, usingthe procedure described in paragraph(e)(2) of that section.

[39 FR 19149, May 30, 1974, as amended at 42FR 59068, Nov. 15, 1977; 50 FR 19921, May 13,1985]

§ 452.110b Erythromycin enteric-coat-ed tablets.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromyin enteric-coatedtablets are enteric-coated tablets com-posed of erythromycin, suitable andharmless buffer substances, diluents,binders, lubricants, colorings, andflavorings. Each tablet contains 100,250, 333, or 500 milligrams of erythro-mycin. Its potency is satisfactory if itis not less than 90 percent and notmore than 120 percent of the number ofmilligrams of erythromycin that it isrepresented to contain. The tabletsshall disintegrate within 2 hours. Themoisture content is not more than 6percent. The erythromycin base used inmaking the batch conforms to thestandards of § 452.10(a)(1) (i), (iii), (iv),(v), (vii), and (viii).




the batch for potency, moisture, pH,residue on ignition, crystallinity, andidentity.

(b) The batch for potency, moisture,and disintegration time.





925

Food and Drug Administration, HHS § 452.110d

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Blend a representa-tive number of tablets in a high-speedglass blender for 2 to 3 minutes with200 milliliters of methyl alcohol. Add300 milliliters of 0.1M potassium phos-phate buffer, pH 8.0 (solution 3), andblend again for 2 to 3 minutes. Furtherdilute with solution 3 to the referenceconcentration of 1.0 microgram oferythromycin base per milliliter (esti-mated).



[39 FR 14149, May 30, 1974, as amended at 44FR 30332, May 25, 1979; 44 FR 48190, Aug. 17,1979; 46 FR 44442, Sept. 4, 1981; 47 FR 15326,Apr. 9, 1982; 50 FR 19921, May 13, 1985]

§ 452.110c Erythromycin capsules.(a) Requirements for certification—(1)

Standards of identity, strength, quality,and purity. Erythromycin capsules arecapsules containing enteric-coatederythromycin pellets, suitable andharmless buffer substances, diluents,binders, lubricants, and colorings. Eachcapsule contains either 125 milligramsor 250 milligrams of erythromycin. Itspotency is satisfactory if it is not lessthan 90 percent and not more than 115percent of the number of milligrams oferythromycin that it is represented tocontain. The moisture content is notmore than 7.5 percent. It passes theacid resistance/dissolution test. Theerythromycin used conforms to thestandards prescribed by § 452.10(a)(1),except heavy metals.




the batch for potency, moisture, pH,residue on ignition, identity, and crys-tallinity.

(b) The batch for potency, moisture,and acid resistance/dissolution.


the batch: 10 packages, each containingapproximately 500 milligrams.

(b) The batch: A minimum of 100 cap-sules.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Place a representativenumber of capsules into a high-speedglass blender jar containing 200 milli-liters of methyl alcohol. Blend for 2 to3 minutes. Add 300 milliliters of 0.1Mpotassium phosphate buffer, pH 8.0 (so-lution 3), and blend again for 2 to 3minutes. Further dilute an aliquotwith solution 3 to the reference con-centration of 1.0 microgram of erythro-mycin base per milliliter (estimated).

(2) Moisture. Proceed as directed in§ 436.201 of this chapter, using the sam-ple preparation method described inparagraph (d)(1) of that section.

(3) Acid resistance/dissolution. Proceedas directed in § 436.542 of this chapter.The quantity Q (the amount of eryth-romycin dissolved) is 85 percent at 45minutes.

[46 FR 16678, Mar. 13, 1981; 46 FR 22359, Apr.17, 1981, as amended at 50 FR 19921, May 13,1985; 50 FR 36992, Sept. 11, 1985; 50 FR 47214,Nov. 15, 1985]

§ 452.110d Erythromycin particles intablets.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin particles intablets are tablets containing erythro-mycin acid-resistant coated particles,suitable and harmless diluents, bind-ers, lubricants, and colorings. Eachtablet contains 333 milligrams of eryth-romycin. Its potency is satisfactory ifit is not less than 90 percent and notmore than 120 percent of the number ofmilligrams of erythromycin that it isrepresented to contain. The loss ondrying is not more than 5.0 percent. Itpasses the dissolution test and the acidresistance test. The erythromycin usedconforms to the standards prescribedby § 452.10(a)(1), except heavy metals.



926

21 CFR Ch. I (4–1–98 Edition)§ 452.115



the batch for potency, safety, mois-ture, pH, residue on ignition, identity,and crystallinity.

(b) The batch for potency, loss ondrying, dissolution, and acid resist-ance.


(a) The erythromycin used in makingthe batch: 10 packages, each containingapproximately 500 milligrams.


(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Place a representativenumber of tablets into a high-speedglass blender jar containing 200 milli-liters of methyl alcohol. Blend for 2 to3 minutes. Add 300 milliliters of 0.1Mpotassium phosphate buffer, pH 8.0 (so-lution 3), and blend again for 2 to 3minutes. Further dilute an aliquotwith solution 3 to the reference con-centration of 1.0 microgram of erythro-mycin base per milliliter (estimated).


(3) Dissolution. Proceed as directed in§ 436.215 of this chapter. The quantity Q(the amount of erythromycin dis-solved) is 75 percent at 45 minutes.

(4) Acid resistance. Proceed as directedin § 436.545 of this chapter. The quan-tity of erythromycin dissolved is notmore than 25 percent at 60 minutes.

[51 FR 37723, Oct. 24, 1986, as amended at 55FR 11584, Mar. 29, 1990]

§ 452.115 Erythromycin estolate oraldosage forms.

§ 452.115a Erythromycin estolate tab-lets.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin estolate tab-lets are composed of erythromycinestolate with one or more suitable andharmless diluents, binders, lubricants,and colorings. Each tablet contains

erythromycin estolate equivalent to500 milligrams of erythromycin. Its po-tency is satisfactory if it is not lessthan 90 percent and not more than 120percent of the number of milligrams oferythromycin that it is represented tocontain. The moisture content is notmore than 5 percent. The tablets shalldisintegrate within 30 minutes. Theerythromycin estolate used conformsto the standards prescribed by§ 452.15(a)(1).



(i) Results of tests and assays on:(a) The erythromycin estolate used

in making the batch for potency, mois-ture, pH, identity, and crystallinity.

(b) The batch for potency, moisture,and disintegration time.

(ii) Samples required:(a) The erythromycin estolate used

in making the batch: 10 packages, eachcontaining approximately 300 milli-grams.

(b) The batch. A minimum of 36 tab-lets.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Place a representativenumber of tables into a high-speedglass blender jar with 200 milliliters ofmethyl alcohol. Blend for 3 to 5 min-utes. Add 300 milliliters of 0.1M potas-sium phosphate buffer, pH 8.0 (solution3), and blend again for 3 to 5 minutes.Hydrolyze a portion of this solution ina 60° C. constant temperature waterbath for 2 hours or at room tempera-ture for 16 to 18 hours. Further dilutewith solution 3 to the reference con-centration of 1.0 microgram of erythro-mycin base per milliliter (estimated).





927

Food and Drug Administration, HHS § 452.115c

§ 452.115b Erythromycin estolate cap-sules.

(a) Requirements for certification—(1)Standards of identity, quality, and purity.Erythromycin estolate capsules arecapsules containing erythromycinestolate with suitable and harmlessbuffer substances and diluents enclosedin a gelatin capsule. The erythromycinestolate content of each capsule isequivalent to either 250 milligrams oferythromycin or 125 milligrams oferythromycin. Its potency is satisfac-tory if it is not less than 90 percent andnot more than 115 percent of the num-ber of milligrams of erythromycin thatit is represented to contain. The mois-ture content is not more than 5 per-cent. The erythromycin estolate usedconforms to the standards prescribedtherefor by § 452.15(a)(1).


(3) Requests for certification; samples.In addition to the requirements of§ 431.1 of this chapter, each such re-quest shall contain;


in making the batch for potency, pH,moisture, crystallinity, and identity.

(b) The batch for potency and mois-ture.


in making the batch: 10 packages, eachcontaining not less than 300 milli-grams.


(b) Test and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Blend a representa-tive number of capsules in a high-speedglass blender with 200 milliliters ofmethyl alcohol for 2 to 3 minutes. Add300 milliliters of 0.1M potassium phos-phate buffer, pH 8.0 (solution 3), andblend again for 2 to 3 minutes. Hydro-lyze a portion of this solution in a 60°C. constant temperature water bath for2 hours or at room temperature for 16to 18 hours. Further dilute with solu-tion 3 to the reference concentration of1.0 microgram of erythromycin baseper milliliter (estimated).



§ 452.115c Erythromycin estolate oralsuspension.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin estolate oralsuspension is erythromycin estolatewith suitable and harmless buffer sub-stances, dispersing agents, diluents,coloring, and flavorings. Each milli-liter contains erythromycin estolateequivalent to 25, 50, or 100 milligramsof erythromycin. Its potency is satis-factory if it is not less than 90 percentand not more than 115 percent of thenumber of milligrams of erythromycinthat it is represented to contain. Its pHis not less than 3.5 and not more than6.5. The erythromycin estolate usedconforms to the standards prescribedby § 452.15(a)(1).

(2) Labeling. In addition to conform-ing with the requirements of § 432.5 ofthis chapter, each package shall bearon its outside wrapper or container andthe immediate container the statement‘‘Refrigerate’’ or ‘‘Keep under refrig-eration’’.



in making the batch for potency, mois-ture, pH, crystallinity, and identity.

(b) The batch for potency and pH.(ii) Samples required:(a) The erythromycin estolate used

in making the batch: 10 containers,each having not less than 300 milli-grams.

(b) The batch: A minimum of six im-mediate containers.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Remove an accuratelymeasured representative volume of thesuspension and dilute with sufficientmethyl alcohol to give a concentrationof 2.5 milligrams per milliliter (esti-mated). Dilute the entire mixture withsufficient 0.1M potassium phosphatebuffer, pH 8.0 (solution 3), to give a


928

21 CFR Ch. I (4–1–98 Edition)§ 452.115d

concentration of 1.0 milligram oferythromycin base per milliliter (esti-mated). Hydrolyze in a 60° C. constanttemperature water bath for 2 hours orat room temperature for 16 to 18 hours.Further dilute with solution 3 to thereference concentration of 1.0microgram of erythromycin base permilliliter (estimated).

(2) pH. Proceed as directed in § 436.202of this chapter, using the drug as it isprepared for dispensing.


§ 452.115d Erythromycin estolate fororal suspension.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin estolate fororal suspension is a dry mixture oferythromycin estolate with suitableand harmless buffer substances, dis-persing agents, diluents, colorings, andflavorings. The erythromycin estolatecontent is 25 milligrams of erythro-mycin per milliliter of the reconsti-tuted suspension. Its potency is satis-factory if it is not less than 90 percentand not more than 115 percent of thenumber of milligrams of erythromycinthat it is represented to contain. Whenreconstituted as directed in its label-ing, its pH is not less than 5.0 and notmore than 7.0. Its moisture content isnot more than 2.0 percent. The erythro-mycin estolate used conforms to thestandards of § 452.15(a)(1).





(b) The batch: Potency, moisture, andpH.


in making the batch: 10 immediatecontainers, each consisting of 300 milli-grams.

(b) The batch: A minimum of 6 imme-diate containers.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Reconstitute the sam-ple as directed in the labeling. With-draw an accurately measured rep-resentative volume of the reconsti-tuted suspension and add sufficientmethyl alcohol to give a concentrationof 2.5 milligrams of erythromycin baseper milliliter (estimated). Dilute thisentire mixture with sufficient 0.1M po-tassium phosphate buffer, pH 8.0 (solu-tion 3), to give a concentration of 1.0milligram of erythromycin base permilliliter (estimated). Hydrolyze in a60° C. constant temperature water bathfor 2 hours or at room temperature for16 to 18 hours. Further dilute with solu-tion 3 to the reference concentration of1.0 microgram of erythromycin baseper milliliter (estimated).

(2) Moisture. Proceed as directed in§ 436.201 of this chapter, using the drypowder.

(3) pH. Proceed as directed in § 436.202of this chapter, using the drug recon-stituted as directed in its labeling.


§ 452.115e Erythromycin estolate forpediatric drops.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin estolate forpediatric drops is a dry mixture oferythromycin estolate with suitableand harmless dispersing agents, buffersubstances, diluents, colorings, andflavorings. When reconstituted as di-rected in the labeling, each millilitercontains the equivalent of 100 milli-grams of erythromycin. Its potency issatisfactory if it is not less than 90 per-cent and not more than 115 percent ofthe number of milligrams of erythro-mycin that it is represented to contain.Its moisture content is not more than2.0 percent. Its pH is not less than 5.0nor more than 5.5. The erythromycinestolate used conforms to the stand-ards prescribed by § 452.15(a)(1).


(3) Requests for certification; samples.In addition to the requirements of


929

Food and Drug Administration, HHS § 452.115g

§ 431.1 of this chapter, each such re-quest shall contain:


in making the batch for potency, pH,moisture, crystallinity, and identity.

(b) The batch for potency, moisture,and pH.


in making the batch: 10 packages, eachcontaining not less than 300 milli-grams.


(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Reconstitute the sam-ple as directed in the labeling. With-draw an accurately measured rep-resentative volume of the reconsti-tuted suspension and add sufficientmethyl alcohol to give a concentrationof 2.5 milligrams of erythromycin baseper milliliter (estimated). Dilute thisentire mixture with sufficient 0.1M po-tassium phosphate buffer, pH 8 (solu-tion 3), to give a concentration of 1.0milligram of erythromycin base permilliliter (estimated). Hydrolyze in a60° C. constant temperature water bathfor 2 hours or at room temperature for16 to 18 hours. Further dilute with solu-tion 3 to the reference concentration of1.0 microgram of erythromycin baseper milliliter (estimated).


(3) pH. Proceed as directed in§ 436.202(b) of this chapter, using thesuspension prepared as directed in thelabeling.


§ 452.115f Erythromycin estolatechewable tablets.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin estolatechewable tablets are tablets composedof erythromycin estolate and suitableand harmless diluents, binders, buffers,colorings, and flavorings. Each tabletcontains erythromycin estolate equiva-lent to either 125 or 250 milligrams oferythromycin. Its potency is satisfac-tory if it is not less than 90 percent and

not more than 115 percent of the num-ber of milligrams of erythromycin thatit is represented to contain. The mois-ture content is not more than 4 per-cent. The erythromycin estolate usedin making the batch conforms to thestandards prescribed by § 452.15(a)(1).

(2) Labeling. It shall be labeled in ac-cordance with § 432.5 of this chapter.






in making the batch: 10 packages, eachconsisting of not less than 300 milli-grams.


(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Blend a representa-tive number of tablets in a high-speedglass blender for 2 to 3 minutes in 200milliliters of methyl alcohol. Add 300milliliters of 0.1M potassium phosphatebuffer, pH 8.0 (solution 3), and blendagain for 2 to 3 minutes. Hydrolyze thissolution in a 60° C. constant tempera-ture water bath for 2 hours or at roomtemperature for 16 to 18 hours. Furtherdilute with solution 3 to the referenceconcentration of 1.0 microgram oferythromycin base per milliliter (esti-mated).



§ 452.115g Erythromycin estolate andsulfisoxazole acetyl oral suspension.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin estolate andsulfisoxazole acetyl oral suspension iserythromycin estolate andsulfisoxazole acetyl with suitable andharmless buffer substances, preserva-tives, solvents, stabilizers, emulsifiers,dispersing agents, colorings, and


930

21 CFR Ch. I (4–1–98 Edition)§ 452.125

flavorings. Each milliliter containserythromycin estolate equivalent to 25milligrams of erythromycin and 120milligrams of sulfisoxazole. Its eryth-romycin content is satisfactory if it isnot less than 90 percent and not morethan 120 percent of the number of milli-grams of erythromycin that it is rep-resented to contain. Its sulfisoxazoleacetyl content is satisfactory if it isnot less than 90 percent and not morethan 115 percent of the number of milli-grams of sulfisoxazole that it is rep-resented to contain. Its pH is not lessthan 3.5 and not more than 6.5. Theerythromycin estolate used conformsto the standards prescribed by§ 452.15(a)(1). The sulfisoxazole acetylused conforms to the standards pre-scribed by the U.S.P. XXII.



(i) Results of tests and assays on:(A) The erythromycin estolate used


(B) The sulfisoxazole acetyl used inmaking the batch for all U.S.P. XXIIspecifications.

(C) The batch for erythromycin con-tent, sulfisoxazole content, and pH.

(ii) Samples, if required by the Cen-ter for Drug Evaluation and Research:

(A) The erythromycin estolate usedin making the batch: 10 packages, eachcontaining not less than 500 milli-grams.

(B) The batch: a minimum of 15 im-mediate containers.

(b) Tests and methods of assay—(1)Erythromycin content. Proceed as di-rected in § 436.105 of this chapter, pre-paring the sample for assay as follows:Remove an accurately measured rep-resentative volume of the suspensionand dilute with sufficient methyl alco-hol to give a concentration of 2.5 milli-grams per milliliter (estimated). Dilutethe entire mixture with sufficient 0.1Mpotassium phosphate buffer, pH 8.0 (so-lution 3), to give a concentration of 1.0milligram of erythromycin base permilliliter (estimated). Hydrolyze in a60 °C constant temperature water bath

for 2 hours or at room temperature for16 to 18 hours. Further dilute with solu-tion 3 to the reference concentration of1.0 microgram of erythromycin baseper milliliter (estimated).

(2) Sulfisoxazole content. Proceed asdirected in § 436.328 of this chapter.

(3) pH. Proceed as directed in § 436.202of this chapter, using the drug as it isprepared for dispensing.

[55 FR 280, Jan. 4, 1990]

§ 452.125 Erythromycin ethylsuccinateoral dosage forms.

§ 452.125a Erythromycinethylsuccinate chewable tablets.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycinethylsuccinate chewable tablets arecomposed of erythromycinethylsuccinate and suitable and harm-less diluents, binders, buffers, color-ings, and flavorings. Each tablet con-tains erythromycin ethylsuccinateequivalent to 200 milligrams of eryth-romycin. Its potency is satisfactory ifit is not less than 90 percent and notmore than 120 percent of the number ofmilligrams of erythromycin that it isrepresented to contain. The moisturecontent is not more than 5 percent.The erythromycin ethylsuccinate usedconforms to the standards prescribedby § 452.25(a)(1).

(2) Labeling. In addition to the label-ing requirements prescribed by § 432.5of this chapter, this drug shall be la-beled ‘‘erythromycin ethylsuccinatetablets’’.


(i) Results of tests and assays on:(a) The erythromycin ethylsuccinate

used in making the batch for potency,moisture, pH, residue on ignition, iden-tity, and crystallinity.


(ii) Samples required:(a) The erythromycin ethylsuccinate

used in making the batch: 10 packages,each consisting of 500 milligrams.



931

Food and Drug Administration, HHS § 452.125c

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Blend a representa-tive number of tablets in a high-speedglass blender for 2 to 3 minutes with200 milliliters of methyl alcohol. Add300 milliliters of 0.1M potassium phos-phate buffer, pH 8.0 (solution 3), andblend again for 2 to 3 minutes. Furtherdilute with solution 3 to the referenceconcentration of 1.0 microgram oferythromycin base per milliliter (esti-mated).


[39 FR 19149, May 30, 1974, as amended at 41FR 51596, Nov. 23, 1976; 42 FR 29858, June 10,1977; 50 FR 19921, May 13, 1985]

§ 452.125b Erythromycinethylsuccinate oral suspension.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycinethylsuccinate oral suspension iserythromycin ethylsuccinate with suit-able and harmless buffer substances,dispersing agents, diluents, colorings,flavorings, and preservatives. Eachmilliliter contains erythromycinethylsuccinate equivalent to 40 or 80milligrams of erythromycin. Its po-tency is satisfactory if it is not lessthan 90 percent and not more than 120percent of the number of milligrams oferythromycin that it is represented tocontain. Its pH is not less than 6.5 andnot more than 8.5. The erythromycinethylsuccinate used conforms to thestandards prescribed by § 452.25(a)(1).




used in making the batch for potency,moisture, pH, identity, residue on igni-tion, and crystallinity.

(b) The batch for potency and pH.(ii) Samples required:(a) The erythromycin ethylsuccinate

used in making the batch: 10 contain-ers each consisting of 500 milligrams.


(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Place an accuratelymeasured representative volume of thesuspension into a high-speed glassblender jar and add sufficient methylalcohol to give a concentration of 1.0milligram of erythromycin base permilliliter (estimated). Blend for 3 to 5minutes. Further dilute with 0.1M po-tassium phosphate buffer, pH 8.0 (solu-tion 3), to the reference concentrationof 1.0 microgram of erythromycin baseper milliliter (estimated).

(2) pH. Proceed as directed in § 436.202of this chapter, using the undiluteddrug.


§ 452.125c Erythromycinethylsuccinate for oral suspension.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycinethylsuccinate for oral suspension is adry mixture of erythromycinethylsuccinate with suitable and harm-less buffer substances, dispersingagents, diluents, colorings, andflavorings. It contains the equivalentof 40 milligrams or 80 milligrams oferythromycin per milliliter of the re-constituted suspension. Its potency issatisfactory if it is not less than 90 per-cent and not more than 120 percent ofthe number of milligrams of erythro-mycin that it is represented to contain.Its loss on drying is not more than 1percent. When reconstituted as di-rected in the labeling, its pH is not lessthan 7.0 nor more than 9.0. The crys-talline erythromycin ethylsuccinateused conforms to the standards pre-scribed by § 452.25(a)(1).




used in making the batch for potency,


932

21 CFR Ch. I (4–1–98 Edition)§ 452.125d

moisture, pH, residue on ignition, iden-tity, and crystallinity.

(b) The batch, for potency, pH, andloss on drying.


used in making the batch: 10 contain-ers each consisting of approximately500 milligrams.


(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Reconstitute as di-rected in the labeling. Place an accu-rately measured representative portionof the sample into a high-speed glassblender jar containing sufficient meth-yl alcohol to give a final volume of 200milliliters. Blend for 3 to 5 minutes.Further dilute an aliquot with 0.1M po-tassium phosphate buffer, pH 8.0 (solu-tion 3), to the reference concentrationof 1.0 microgram of erythromycin baseper milliliter (estimated).

(2) pH. Proceed as directed in § 436.202of this chapter, using the suspensionprepared as directed in the labeling. Ifthe suspension contains 80 milligramsper milliliter, equilibrium usually isreached in approximately 15 minutes.


[39 FR 19149, May 30, 1974, as amended at 47FR 21240, May 18, 1982; 50 FR 19921, May 13,1985]

§ 452.125d Erythromycinethylsuccinate tablets.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycinethylsuccinate tablets are composed oferythromycin ethylsuccinate and suit-able and harmless diluents, binders,buffers, and colorings. Each tablet con-tains erythromycin ethylsuccinateequivalent to 400 milligrams of eryth-romycin. Its potency is satisfactory ifit is not less than 90 percent and notmore than 120 percent of the number ofmilligrams of erythromycin that it isrepresented to contain. The loss ondrying is not more than 4.0 percent.The tablets shall disintegrate within 40minutes. The erythromycinethylsuccinate used conforms to thestandards prescribed by § 452.25(a)(1).





(b) The batch for potency, loss ondrying, and disintegration time.


used in making the batch: 10 packages,each containing approximately 500 mil-ligrams.


(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Place a representativenumber of tablets into a high-speedglass blender jar containing sufficientmethyl alcohol to yield a concentra-tion of 5 milligrams of erythromycinactivity or less per milliliter whenblended. Blend for 3 to 5 minutes. Fur-ther dilute an aliquot of this solutionwith 0.1M potassium phosphate buffer,pH 8.0 (solution 3), to the referenceconcentration of 1.0 microgram oferythromycin base per milliliter (esti-mated).

(2) Loss on drying. Proceed as directedin § 436.200(a) of this chapter.

(3) Disintegration time—(i) If the tabletis uncoated. Proceed as directed in§ 436.212 of this chapter, using the pro-cedure described in paragraph (e)(1) ofthat section.

(ii) If the tablet is plain-coated. Pro-ceed as directed in § 436.212 of this chap-ter, using the procedure described inparagraph (e)(2) of that section.

[41 FR 51596, Nov. 23, 1976, as amended at 50FR 19921, May 13, 1985; 55 FR 14091, Apr. 16,1990]

§ 452.125e Erythromycinethylsuccinate-sulfisoxazole acetylfor oral suspension.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycinethylsuccinate-sulfisoxazole acetyl for


933


oral suspension is a dry mixture oferythromycin ethylsuccinate andsulfisoxazole acetyl with suitable andharmless flavorings, buffers,surfactants, colorings, and suspendingagents. When reconstituted as directedin the labeling, each milliliter will con-tain erythromycin ethylsuccinateequivalent to 40 milligrams of erythro-mycin and sulfisoxazole acetyl equiva-lent to 120 milligrams of sulfisoxazole.Its erythromycin ethylsuccinate con-tent is satisfactory if it is not less than90 percent and not more than 120 per-cent of the number of milligrams oferythromycin that it is represented tocontain. Its sulfisoxazole acetyl con-tent is satisfactory if it is not less than90 percent and not more than 115 per-cent of the number of milligrams ofsulfisoxazole that it is represented tocontain. Its loss on drying is not morethan 1.0 percent. When reconstituted asdirected in the labeling, its pH is notless than 5.0 and not more than 7.0. Theerythromycin ethylsuccinate used con-forms to the standards prescribed by§ 452.25(a)(1). The sulfisoxazole acetylused conforms to the standards pre-scribed by the U.S.P.





(b) The sulfisoxazole acetyl used inmaking the batch for all U.S.P. speci-fications.

(c) The batch for erythromycin con-tent, sulfisoxazole content, loss on dry-ing, and pH.


used in making the batch: 10 packageseach containing approximately 500 mil-ligrams.

(b) The batch: A minimum of 10 im-mediate containers.

(b) Tests and methods of assay—(1)Erythromycin content. Proceed as di-rected in § 436.105 of this chapter, pre-paring the sample for assay as follows:

Reconstitute the sample as directed inthe labeling. Allow to stand for 1 hour.Shake gently and transfer 5 millilitersof the well-shaken suspension into ahigh-speed glass blender jar containing195 milliliters of methyl alcohol. Blendfor 3 to 5 minutes. Further dilute an al-iquot with 0.1M potassium phosphatebuffer, pH 8.0 (solution 3), to the ref-erence concentration of 1.0 microgramof erythromycin base per milliliter (es-timated).

(2) Sulfisoxazole acetyl content. Pro-ceed as directed in § 436.328 of this chap-ter.


(4) pH. Proceed as directed in § 436.202of this chapter, using the suspensionreconstituted as directed in the label-ing.

[46 FR 2990, Jan. 13, 1981, as amended at 50FR 19921, May 13, 1985]

§ 452.135 Erythromycin stearate oraldosage forms.

§ 452.135a Erythromycin stearate tab-lets.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin stearate tab-lets are tablets composed of erythro-mycin stearate with suitable andharmless buffer substances, diluents,binders, lubricants, colorings, andflavorings. Each tablet contains eryth-romycin stearate equivalent to 75, 100,125, 250, or 500 milligrams of erythro-mycin. Its potency is satisfactory if itis not less than 90 percent and notmore than 120 percent of the number ofmilligrams of erythromycin that it isrepresented to contain. Tablets shalldisintegrate within 11⁄2 hours. The losson drying is not more than 5.0 percent.The erythromycin stearate used inmaking the tablets conforms to thestandards prescribed by § 452.35(a)(1).



(i) Results of tests and assays on:(a) The erythromycin stearate used

in making the batch for potency, pH,


934

21 CFR Ch. I (4–1–98 Edition)§ 452.135b

moisture, residue on ignition, crys-tallinity, and identity.

(b) The batch for potency, loss ondrying, and disintegration time.

(ii) Samples required:(a) The erythromycin stearate used

in making the batch: 10 containers,each consisting of not less than 500milligrams.


(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Blend a representa-tive number of tablets in a high-speedglass blender with 200 milliliters ofmethyl alcohol for 3 to 5 minutes. Add300 milliliters of 0.1M potassium phos-phate buffer, pH 8.0 (solution 3), andblend again for 3 to 5 minutes. Furtherdilute with solution 3 to the referenceconcentration of 1.0 microgram oferythromycin base per milliliter (esti-mated).



[39 FR 19149, May 30, 1974, as amended at 42FR 59068, Nov. 15, 1977; 50 FR 19921, May 13,1985]

§ 452.135b Erythromycin stearate oralsuspension.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin stearate oralsuspension is erythromycin stearatewith suitable and harmless buffer sub-stances, dispersing agents, diluents,colorings, and flavorings. It containsthe equivalent of 25 milligrams oferythromycin per milliliter. Its po-tency is satisfactory if it is not lessthan 90 percent and not more than 120percent of the number of milligrams oferythromycin that it is represented tocontain. Its pH is not less than 7.0 andnot more than 8.5. The erythromycinstearate used conforms to the stand-ards prescribed by § 452.35(a)(1).


(3) Requests for certification; samples.In addition to complying with the re-

quirements of § 431.1 of this chapter,each such request shall contain:


in making the batch for potency, mois-ture, pH, residue on ignition, identity,and crystallinity.

(b) The batch for potency and pH.(ii) Samples required:(a) The erythromycin stearate used



(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Place an accuratelymeasured representative volume of thesuspension into a high-speed glassblender jar. Add sufficient methyl alco-hol to the jar to give a concentrationof 1.25 milligrams of erythromycin baseper milliliter (estimated). Blend for 2to 3 minutes. Add sufficient 0.1M potas-sium phosphate buffer, pH 8.0 (solution3), to give a concentration of 0.5 milli-grams of erythromycin base per milli-liter (estimated) and blend again for 2to 3 minutes. Further dilute with solu-tion 3 to the reference concentration of1.0 microgram of erythromycin baseper milliliter (estimated).

(2) pH. Proceed as directed in § 436.202of this chapter, using the undilutedsuspension.


§ 452.135c Erythromycin stearate fororal suspension.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin stearate fororal suspension is a dry mixture oferythromycin stearate with suitableand harmless buffer substances, dis-persing agents, diluents, colorings, andflavorings. It contains the equivalentof 25 or 50 milligrams of erythromycinper milliliter of the reconstituted sus-pension. Its potency is satisfactory if itis not less than 90 percent and notmore than 120 percent of the number ofmilligrams of erythromycin that it isrepresented to contain. Its moisturecontent is not more than 2 percent.When reconstituted as directed in the


935


labeling, its pH is not less than 6.0 andnot more than 9.0. The erythromycinstearate used conforms to the stand-ards prescribed by § 452.35(a)(1).




in making the batch for potency, mois-ture, pH, residue on ignition, identity,and crystallinity.

(b) The batch for potency, moisture,and pH.

(ii) Samples required:(a) The erythromycin stearate used



(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Reconstitute as di-rected in the labeling. Place an accu-rately measured representative portionof the suspension into a high-speedglass blender jar with sufficient methylalcohol to give a concentration of 1.0milligram of erythromycin base permilliliter (estimated). Blend for 3 to 5minutes. Further dilute with 0.1M po-tassium phosphate buffer, pH 8.0 (solu-tion 3), to the reference concentrationof 1.0 microgram of erythromycin baseper milliliter (estimated).


(3) pH. Proceed as directed in § 436.202of this chapter, using the suspensionobtained when the drug is reconsti-tuted as directed in the labeling.

[40 FR 49083, Oct. 21, 1975, as amended at 41FR 24884, June 21, 1976; 50 FR 19921, May 13,1985]

§ 452.150 Clarithromycin oral dosageforms.

§ 452.150a Clarithromycin tablets.(a) Requirements for certification—(1)

Standards of identity, strength, quality,and purity. Clarithromycin tablets arecomposed of clarithromycin and one or

more suitable and harmless diluents,binders, lubricants, colorings, andflavorings. Each tablet contains 250milligrams or 500 milligrams ofclarithromycin activity. Itsclarithromycin content is satisfactoryif it is not less than 90 percent and notmore than 110 percent of the number ofmilligrams of clarithromycin that it isrepresented to contain. The loss ondrying is not more than 6.0 percent. Itpasses the dissolution test. It passesthe identity test. The clarithromycinused conforms to the standards pre-scribed by § 452.50(a)(1).


(3) Requests for certification samples. Inaddition to complying with the re-quirements of § 431.1 of this chapter,each such request shall contain:

(i) Results of tests and assays on:(A) The clarithromycin used in mak-

ing the batch for potency, moisture,pH, residue on ignition, heavy metals,specific rotation, identity, and crys-tallinity.

(B) The batch for content, loss ondrying, dissolution, and identity.


(A) The clarithromycin used in mak-ing the batch: 10 packages, each con-taining approximately 500 milligrams.

(B) The batch: A minimum of 100 tab-lets.

(b) Tests and methods of assay—(1)Clarithromycin content. Proceed as di-rected in § 452.50(b)(1), preparing thesample solution and calculating theclarithromycin content as follows:

(i) Preparation of sample solution.Grind and composite five whole tabletsin a glass mortar and pestle and quan-titatively transfer the powder to a 500-milliliter volumetric flask with 50 mil-liliters of distilled water and shake me-chanically until the tablets are welldispersed (approximately 5 to 10 min-utes). Add 300 milliliters of methanoland shake mechanically for 30 minutes.Dilute with methanol to volume andmix. Allow the excipients to settle.Quantitatively transfer and dilute aconvenient aliquot of the supernatantwith mobile phase (described in§ 452.50(b)(1)(i)) to obtain a solution


936

21 CFR Ch. I (4–1–98 Edition)§ 452.150b

containing 125 micrograms ofclarithromycin per milliliter (esti-mated). Filter through a suitable filtercapable of removing particulate matter0.5 micron in diameter.

(ii) Calculations. Calculate theclarithromycin content as follows:

Milligramsclarithromycin per

tablet

of

A P d

A n

U s

s

=× ×

× ×1 000,where:AU = Area of the clarithromycin peak (at a

retention time equal to that observed forthe clarithromycin standard) in the chro-matogram of the sample;

AS = Area of the clarithromycin peak in thechromatogram of the clarithromycinworking standard;

PS = Clarithromycin activity in theclarithromycin working standard solu-tion in micrograms per milliliter;

d = Dilution factor of the sample; andn = Number of tablets in the sample.

(2) Loss on drying. Proceed as directedin § 436.200(c) of this chapter, using asample weight of 1 to 2 grams.

(3) Dissolution. Proceed as directed in§ 436.215 of this chapter. The quantity Q(the amount of clarithromycin dis-solved) is 80 percent at 30 minutes.

(4) Identity. Using the high-perform-ance liquid chromatographic proceduredescribed in paragraph (b)(1) of thissection, the retention time for thepeak of the active ingredient must bewithin 2 percent of the retention timefor the peak of the corresponding ref-erence standard.

[58 FR 26654, May 4, 1993. Redesignated at 61FR 34726, July 3, 1996]

§ 452.150b Clarithromycin granules fororal suspension.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Clarithromycin granules fororal suspension is a dry mixture con-taining clarithromycin-coated par-ticles, suitable and harmless dispersingagents, diluents, preservatives, andflavorings. It contains the equivalentof 25 or 50 milligrams ofclarithromycin activity per milliliterof the reconstituted suspension. Its po-tency is satisfactory if it is not lessthan 90 percent and not more than 115percent of the number of milligrams ofclarithromycin that it is represented

to contain. Its loss on drying is notmore than 2.0 percent. When con-stituted as directed in the labeling, itspH is not less than 4.0 nor more than5.4. The clarithromycin used conformsto the standards prescribed by§ 452.50(a)(1).



(i) Results of tests and assays on:(A) The clarithromycin used in mak-

ing the batch for potency, moisture,pH, residue on ignition, heavy metals,specific rotation, identity, and crys-tallinity.

(B) The batch for content, loss ondrying, pH, and identity.


(A) The clarithromycin used in mak-ing the batch: 10 packages, each con-taining approximately 500 milligrams.

(B) The batch: A minimum of six im-mediate containers.

(b) Tests and methods of assay—(1)Clarithromycin content. Proceed as di-rected in § 452.50(b)(1), except use aknown injection volume between 10 and60 microliters. Also, prepare the mobilephase, working standard solution, andsample solution, and use system suit-ability requirements and calculation asfollows:

(i) Mobile phase. Add 600 milliliters ofmethanol and 400 milliliters of 0.067Mpotassium phosphate, monobasic, to asuitable container, mix well, and ad-just the pH to 3.5 with phosphoric acid.Filter through a suitable filter capableof removing particulate matter to 0.5micron in diameter. Degas the mobilephase just before its introduction intothe chromatographic system.

(ii) Preparation of standard solution.Dissolve an accurately weighed portionof the clarithromycin working stand-ard in sufficient methanol to obtain asolution having a known concentrationof approximately 2.1 milligrams permilliliter of clarithromycin. Quan-titatively transfer and dilute an ali-quot of this solution with mobile phaseand mix to obtain a solution of known


937


concentration of approximately 415micrograms of clarithromycin per mil-liliter.

(iii) Preparation of sample solution.Constitute as directed in the labeling.Accurately measure a representativeportion of the suspension that containsabout 1 to 2 grams of clarithromycinactivity and, using approximately 330milliliters of 0.067M potassium phos-phate, dibasic, quantitatively transferinto a 1,000 milliliter volumetric flaskcontaining approximately 50 millilitersof 0.067M potassium phosphate, dibasic.Shake for 30 minutes. Dilute to volumewith methanol. Mix well and place inan ultrasonic bath for 30 minutes. Coolto room temperature and adjust to vol-ume with methanol. Add a magneticstirring bar and stir for 60 minutes.Allow excipients to settle and dilute anappropriate aliquot of the solutionwith mobile phase to obtain a solutioncontaining 500 micrograms of

clarithromycin activity per milliliterand mix well. Filter through a suitablefilter capable of removing particulatematter 0.5 micron in diameter.

(iv) System suitability requirements—(A) Tailing factor. The tailing factor (T)is satisfactory if it is not less than 1.0and not greater than 1.7 for theclarithromycin peak.

(B) Efficiency of the column. The effi-ciency (n) is satisfactory if it is greaterthan 2,100 theoretical plates for theclarithromycin peak.

(C) Capacity factor. The capacity fac-tor (k′) is satisfactory if it is between2.5 and 6 for the clarithromycin peak.

(D) Coefficient of variation (relativestandard deviation). The coefficient ofvariation (SR in percent of three rep-licate injections) is satisfactory if it isnot more than 2.0 percent.

(v) Calculations. Calculate theclarithromycin content as follows:

Milligrams ofclarithromycinper milliliter

=AU X PS X D

AS X V

where:AU = Area of the clarithromycin peak

in the chromatogram of the sam-ple;

AS = Area of the clarithromycin peakin the chromatogram of theclarithromycin working standard;

PS = Clarithromycin activity in theclarithromycin working standardsolution in micrograms per milli-liter;

D = Dilution factor of the sample testsolution; and

V = Volume, in milliliters, of the por-tion of suspension taken.

(2) Loss on drying. Proceed as directedin § 436.200(a) of this chapter, using asample weight of approximately 1gram, weighing in a normal laboratoryatmosphere.

(3) pH. Proceed as directed in § 436.202of this chapter, using the suspensionprepared as directed in the labeling.Stir the suspension for 10 minutes withthe electrode immersed and record thepH.

(4) Identity. Using the high-perform-ance liquid chromatographic procedure

described in paragraph (b)(1) of thissection, the retention times for theclarithromycin peak must be within 2percent of the retention time for thepeak of the reference standard.

[61 FR 34726, July 3, 1996]

§ 452.160 Azithromycin oral dosageforms.

§ 452.160a Azithromycin capsules.(a) Requirements for certification—(1)

Standards of identity, strength, quality,and purity. Azithromycin capsules arecomposed of azithromycin and one ormore suitable and harmless diluents,disintegrants, lubricants, and wettingagents enclosed in a gelatin capsule.Each capsule contains azithromycinequivalent to 250 milligrams ofazithromycin. The azithromycin con-tent is satisfactory if it is not less than90 percent and not more than 110 per-cent of the number of milligrams ofazithromycin that it is represented tocontain. The moisture content of thecapsules is not more than 5.0 percent.The capsules pass the dissolution test.


938

21 CFR Ch. I (4–1–98 Edition)§ 452.160b

The capsules pass the identity test.The azithromycin used conforms to thestandards prescribed by § 452.60(a)(1) ofthis part.


(3) Requests for certification; samples.In addition to complying with the re-quirements of § 431.1 of this chapter,each such request shall contain;

(i) Results of tests and assays on:(A) The azithromycin used in making

the batch for potency, moisture, pH,residue on ignition, heavy metals, spe-cific rotation, crystallinity, and iden-tity.

(B) The batch for content, moisture,dissolution, and identity.


(A) The azithromycin used in makingthe batch: 10 packages, each containingapproximately 500 milligrams.

(B) The batch: A minimum of 100 cap-sules.

(b) Tests and methods of assay—(1)Azithromycin content. Proceed as di-rected in § 452.60(b)(1), preparing thesample solution and calculating theazithromycin content as follows:

(i) Preparation of sample solution.Quantitatively transfer the contents ofone capsule into a 250-milliliter volu-metric flask. Add about 175 millilitersof acetonitrile and shake on a recip-rocating shaker for 30 minutes. Diluteto volume with acetonitrile, stopperthe flask and mix well. Place 40 milli-liters of the resulting suspension into asuitably sized centrifuge tube. Stopperthe tube and centrifuge the suspension(about 10 minutes at 1,000 rpm). Pipet2.0 milliliters of the supernatant into a50-milliliter volumetric flask and di-lute to volume with the mobile phase.Pipet 2.0 milliliters of this solutioninto a 25-milliliter volumetric flaskand dilute to volume with mobilephase. The final dilution of the sampleand standard must be identical. Thefinal concentration of azithromycin inthe sample solution is 0.003 milligramper milliliter (estimated).

(ii) Calculations. Calculate theazithromycin content as follows:

Milligramsof azithromycinper capsule =

× ×

×

A P d

A

U S

S 1 000,where:AU = Area of the azithromycin peak (at a re-

tention time equal to that observed forthe azithromycin standard) in the chro-matogram of the sample;

AS = Area of the azithromycin peak of theazithromycin working standard;

PS = Azithromycin activity in theazithromycin working standard solutionin micrograms per milliliter; and

d = Dilution factor of the sample = 250×50×25/2×2.


(3) Dissolution test. Proceed as di-rected in § 436.215 of this chapter. Thequantity Q (the percentage ofazithromycin activity dissolved) is 75percent within 45 minutes.

(4) Identity. Using the high-perform-ance liquid chromatographic proceduredescribed in paragraph (b)(1) of thissection the retention time for the peakof the active ingredient must be with 2percent of the retention time for thepeak of the corresponding referencestandard.

[58 FR 26658, May 4, 1993. Redesignated at 59FR 52078, Oct. 14, 1994.]

§ 452.160b Azithromycin for oral sus-pension.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Azithromycin for oral sus-pension is a dry mixture ofazithromycin with a suitable andharmless buffer substance, sweetener,diluent, anticaking agent, andflavorings. The dry mixture is pack-aged in single dose packets each con-taining 1,000 milligrams ofazithromycin. The azithromycin con-tent is satisfactory if it is not less than90 percent and not more than 110 per-cent of the number of milligrams ofazithromycin that it is represented tocontain. Its moisture content is notmore than 1.5 percent. When con-stituted as directed in the labeling, thepH of the suspension is not less than 9and not more than 11. It gives a posi-tive identity test for azithromycin.The azithromycin used conforms to thestandards prescribed by § 452.60(a)(1).


939



(3) Requests for certification; samples.In addition to complying with the re-quirements of § 431.1 of this chapter,each such request shall contain;

(i) Results of tests and assays on:(A) The azithromycin used in making

the batch for potency, moisture, pH,residue on ignition, heavy metals, spe-cific rotation, crystallinity, and iden-tity.

(B) The batch for content, moisture,pH, and identity.


(A) The azithromycin used in makingthe batch: 10 packages, each containingapproximately 1,000 milligrams.

(B) The batch: A minimum of 30packages.

(b) Tests and methods of assay—(1)Azithromycin content. Proceed as di-rected in § 452.60(b)(1), preparing thedissolving solvent and sample solutionand calculating the azithromycin con-tent as follows:

(i) Dissolving solvent. Dissolve 2.2grams of potassium phosphatemonobasic in 1,590 milliliters ofultrapure deionized or high-perform-ance liquid chromatographic-gradewater. Add 600 milliliters of 2-propanol,480 milliliters of ethanol, and 330 milli-liters of acetonitrile, adjust to pH 8.4with 10M potassium hydroxide andshake on a reciprocating shaker for 30minutes. The dissolving solvent is0.01M monobasic potassium phos-phate:2-propanol:ethanol:acetonitrile(53:20:16:11, by volume).

(ii) Preparation of sample solution.Quantitatively transfer the contents ofone package into a 500-milliliter volu-metric flask. Add about 350 millilitersof dissolving solvent and shake on a re-ciprocating shaker for 30 minutes. Di-lute to volume with dissolving solvent,stopper the flask, and mix well. Place40 milliliters of the resulting suspen-sion into a suitably sized centrifugetube. Stopper the tube and centrifugethe suspension (about 20 minutes at1,000 revolutions per minute). Pipet 10.0milliliters of the diluted solution intoa 50-milliliter volumetric flask and di-lute to volume with mobile phase (de-

scribed in § 452.60(b)(1)(i)). Pipet 2.0 mil-liliters of the diluted solution into a 50-milliliter volumetric flask and diluteto volume with mobile phase. The finaldilution of the sample and standardmust be identical. The final concentra-tion of azithromycin in the sample so-lution is 0.003 milligram per milliliter(estimated).

(iii) Calculations. Calculate theazithromycin content as follows:

MilligramsU s

s

ofazithromycinper package

=× ×

×

A P d

A 1 000,where:AU = Area of the azithromycin peak in the

chromatogram of the sample (at a reten-tion time equal to that observed for theazithromycin standard);

AS = Area of the azithromycin peak in thechromatogram of the azithromycinworking standard;

PS = Azithromycin activity in theazithromycin working standard solutionin micrograms per milliliter; and

d = Dilution factor of the sample = 500 X 50/10 X 50/10 X 50/2.


(3) pH. Proceed as directed in § 436.202of this chapter, using the drug con-stituted as directed in the labeling.Allow the constituted suspension to sitfor 10 minutes undisturbed before mak-ing the measurement.

(4) Identity. Using the high-perform-ance liquid chromatographic proceduredescribed in paragraph (b)(1) of thissection, the retention time for thepeak of the active ingredient must bewithin 2 percent of the retention timefor the peak of the corresponding ref-erence standard.

[59 FR 52078, Oct. 14, 1994]

§ 452.175 Troleandomycin oral dosageforms.

§ 452.175a Troleandomycin capsules.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Troleandomycin capsulesare capsules composed oftroleandomycin and one or more suit-able buffers, diluents, binders, lubri-cants, and colorings. Each capsule con-tains 125 milligrams or 250 milligrams


940

21 CFR Ch. I (4–1–98 Edition)§ 452.175b

of troleandomycin. Its potency is satis-factory if it is not less than 90 percentand not more than 120 percent of thenumber of milligrams oftroleandomycin that it is representedto contain. The loss on drying is notmore than 5 percent. Thetroleandomycin used conforms to thestandards prescribed by § 452.75(a)(1).



(i) Results of tests and assays on:(a) The troleandomycin used in mak-

ing the batch for potency, loss on dry-ing, pH, residue on ignition, identity,Rf value, acetyl value (only if morethan one spot is present in the deter-mination of Rf value), and crystallin-ity.

(b) The batch for potency and loss ondrying.

(ii) Samples required:(a) The troleandomycin used in mak-

ing the batch: 10 packages, nine con-taining approximately equal portionsof not less than 500 milligrams and onecontaining not less than 2 grams.


(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.106 ofthis chapter, preparing the sample forassay as follows: Place a representativenumber of capsules into a high-speedglass blender jar containing sufficient80 percent isopropyl alcohol solution(solution 15) to obtain a stock solutioncontaining 1,000 micrograms oftroleandomycin per milliliter (esti-mated). Blend for 3 to 5 minutes. Fur-ther dilute an aliquot of the stock solu-tion with distilled water to the ref-erence concentration of 25 microgramsof troleandomycin per milliliter (esti-mated).


[39 FR 19149, May 30, 1974, as amended at 48FR 3960, Jan. 28, 1983; 50 FR 19921, May 13,1985]

§ 452.175b Troleandomycin oral sus-pension.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Troleandomycin oral sus-pension is troleandomycin and one ormore suitable buffers, dispersants,flavorings, colorings, and preservativessuspended in a suitable and harmlessvehicle. Each milliliter contains 25milligrams of troleandomycin. Its po-tency is satisfactory if it is not lessthan 90 percent and not more than 125percent of the number of milligrams oftroleandomycin that it is representedto contain. Its pH is not less than 5.0and not more than 8.0. Thetroleandomycin used conforms to thestandards prescribed by § 452.75(a)(1).





(b) The batch for potency and pH.(ii) Samples required:(a) The troleandomycin used in mak-


(b) The batch: A minimum of five im-mediate containers.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.106 ofthis chapter, preparing the sample forassay as follows: Dilute an accuratelymeasured representative portion of thesample with 80 percent isopropyl alco-hol solution (solution 15) to obtain astock solution containing 1,000micrograms of troleandomycin per mil-liliter (estimated). Further dilute analiquot of the stock solution with dis-tilled water to the reference concentra-tion of 25 micrograms oftroleandomycin per milliliter (esti-mated).


941

Food and Drug Administration, HHS § 452.175d

(2) pH. Proceed as directed in § 436.202of this chapter, using the undilutedsample.


§ 452.175c Troleandomycin for oralsuspension.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Troleandomycin for oralsuspension is troleandomycin withsuitable buffers, dispersants, preserva-tives, colorings, and flavorings. Whenthe suspension is prepared as directedin its labeling, each milliliter contains25 milligrams of troleandomycin. How-ever, if it is for pediatric use, each mil-liliter contains 100 milligrams oftroleandomycin. Its potency is satis-factory if it is not less than 90 percentand not more than 120 percent of thenumber of milligrams oftroleandomycin that it is representedto contain. Its loss on drying is notmore than 2 percent. The pH of the sus-pension, when prepared as directed inits labeling, is not less than 5.0 and notmore than 7.0. The troleandomycinused conforms to the standards pre-scribed by § 452.75(a)(1).





(b) The batch for potency, loss ondrying, and pH.

(ii) Samples required:(a) The troleandomycin used in mak-


(b) The batch: A minimum of five im-mediate containers.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.106 of

this chapter, preparing the sample forassay as follows: Reconstitute the drugas directed in the labeling. Dilute anaccurately measured representativeportion of the sample with sufficient 80percent isopropyl alcohol solution (so-lution 15) to obtain a stock solutioncontaining 1,000 micrograms oftroleandomycin per milliliter (esti-mated). Further dilute an aliquot ofthe stock solution with distilled waterto the reference concentration of 25micrograms of troleandomycin per mil-liliter (estimated).


(3) pH. Proceed as directed in § 436.202of this chapter, using the suspensionobtained after reconstituting the drugas directed in its labeling.


§ 452.175d Troleandomycin chewabletablets.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Each troleandomycinchewable tablet contains an amountequivalent to 125 milligrams oftroleandomycin with suitable diluents,binders, buffers, colorings, andflavorings. Its potency is satisfactory ifit is not less than 90 percent and notmore than 125 percent of the number ofmilligrams of troleandomycin that it isrepresented to contain. The loss ondrying is not more than 5 percent. Thetroleandomycin used conforms to thestandards prescribed by § 452.75(a)(1).





(b) The batch for potency and loss ondrying.

(ii) Samples required:


942

21 CFR Ch. I (4–1–98 Edition)§ 452.225

(a) The troleandomycin used in mak-ing the batch: 10 packages, nine con-taining approximately 500 milligramseach and one containing approximately2 grams.


(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.106 ofthis chapter, preparing the sample forassay as follows: Place a representativenumber of tablets into a high-speedglass blender jar with sufficient 80 per-cent isopropyl alcohol solution (solu-tion 15) to obtain a stock solution con-taining 1,000 micrograms oftroleandomycin per milliliter (esti-mated). Blend 3 to 5 minutes. Furtherdilute an aliquot of the stock solutionwith distilled water to the referenceconcentration of 25 micrograms oftroleandomycin per milliliter (esti-mated).


[39 FR 19149, May 30, 1974, as amended at 48FR 3960, Jan. 28, 1983; 48 FR 36571, Aug. 12,1983; 50 FR 19921, May 13, 1985]

Subpart C—Injectable DosageForms

§ 452.225 Erythromycin ethylsuccinateinjection.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycinethylsuccinate injection is erythro-mycin ethylsuccinate andbutylaminobenzoate dissolved in poly-ethylene glycol 400. It contains a suit-able and harmless preservative. Eachmilliliter contains 50 milligrams oferythromycin. Its potency is satisfac-tory if it is not less than 90 percent andnot more than 115 percent of the num-ber of milligrams of erythromycin thatit is represented to contain. It contains2 percent butylaminobenzoate. It issterile. Its moisture content is notmore than 1.5 percent. The erythro-mycin ethylsuccinate used conforms tothe standards prescribed therefore by§ 452.25a(a)(1).

(2) Labeling. In addition to the label-ing requirements prescribed by § 432.5of this chapter, each immediate con-tainer shall bear on its label and label-

ing the statement: ‘‘Warning—Forintramuscular use only’’.




(b) The batch for potency, sterility,and moisture.


used in making the batch: 10 packages,each containing 500 milligrams.


minimum of 10 immediate containers.(2) For sterility testing: 20 immediate

containers, collected at regular inter-vals throughout each filling operation,except that if the product is sterilizedafter filling, a representative sampleconsisting of 10 immediate containersfrom each sterilizer load. If only onesterilizer load is involved, the sampleshall consist of 20 immediate contain-ers.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: By means of a suit-able hypodermic needle and syringe,remove an accurately measured rep-resentative volume of the sample anddilute with sufficient methyl alcoholto give a solution containing 1.0 milli-gram of erythromycin base per milli-liter (estimated). Further dilute with0.1M potassium phosphate buffer, pH8.0 (solution 3), to the reference con-centration of 1.0 microgram of erythro-mycin base per milliliter (estimated).

(2) Sterility. Proceed as directed in§ 436.20 of this chapter, using the meth-od described in paragraph (e)(1) of thatsection, except use a bacterial-reten-tive membrane resistant to the solventpolyethylene glycol 400 and add 1 milli-liter from each immediate containerdirectly to the membrane, thus elimi-nating the preliminary solubilizationstep.

(3) [Reserved]


943

Food and Drug Administration, HHS § 452.232b

(4) Moisture. Proceed as directed in§ 436.201(e)(1) of this chapter.

[39 FR 19149, May 30, 1974, as amended at 50FR 19920, 19921, May 13, 1985]

§ 452.230 Sterile erythromycingluceptate.

The requirements for certificationand the tests and methods of assay forsterile erythromycin gluceptate pack-aged for dispensing are described in§ 452.30a.

[46 FR 16685, Mar. 13, 1981]

§ 452.232 Erythromycin lactobionateinjectable dosage forms.

§ 452.232a Erythromycin lactobionatefor injection.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin lactobionatefor injection is a dry mixture of eryth-romycin lactobionate and a suitablepreservative. It contains the equivalentof 300 milligrams, 500 milligrams, or 1gram of erythromycin per vial. Its po-tency is satisfactory if it is not lessthan 90 percent and not more than 120percent of the number of milligrams oferythromycin that it is represented tocontain. It is sterile. It isnonpyrogenic. Its moisture content isnot more than 5 percent. Its pH is notless than 6.5 and not more than 7.5. Theerythromycin used conforms to thestandards prescribed by § 452.10(a)(1) (i),(iii), (iv), (v), (vi), (vii), and (viii).




the batch for potency, pH, moisture,residue on ignition, heavy metals, andcrystallinity.

(b) The batch for potency, sterility,pyrogens, moisture, pH, and identity.


the batch: 10 containers, each consist-ing of not less than 500 milligrams.


minimum of 12 immediate containers.


(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Reconstitute as di-rected in the labeling. Using a suitablehypodermic needle and syringe, removethe total withdrawable contents fromeach container represented as a single-dose container; or if the labeling speci-fies the amount of potency in a givenvolume of the preparation, withdrawan accurately measured volume fromeach container. Dilute with sterile dis-tilled water to obtain a concentrationof 10 milligrams of erythromycin baseper milliliter (estimated). Further di-lute with 0.1M potassium phosphatebuffer, pH 8.0 (solution 3), to the ref-erence concentration of 1.0 microgramof erythromycin base per milliliter (es-timated).





of this chapter, using a concentrationof 50 milligrams of erythromycin permilliliter.


[39 FR 19149, May 30, 1974, as amended at 50FR 19920, 19921, May 13, 1985. Redesignated at51 FR 35216, Oct. 2, 1986]

§ 452.232b Sterile erythromycinlactobionate.

The requirements for certificationand the tests and methods of assay forsterile erythromycin lactobionatepackaged for dispensing are describedin § 452.32a.

[51 FR 35216, Oct. 2, 1986]


944

21 CFR Ch. I (4–1–98 Edition)§ 452.310

Subpart D—Ophthalmic DosageForms

§ 452.310 Erythromycin ophthalmicointment.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin ophthalmicointment is erythromycin in a suitableand harmless ointment base. Eachgram of ointment contains 5 milli-grams of erythromycin. Its potency issatisfactory if it is not less than 90 per-cent and not more than 120 percent ofthe number of milligrams of erythro-mycin that it is represented to contain.It is sterile. The moisture content isnot more than 1 percent. The erythro-mycin used conforms to the standardsprescribed by § 452.10(a)(1) (i), (iii), (iv),(v), (vii), and (viii).





(b) The batch for potency, sterility,and moisture.




minimum of five immediate contain-ers.

(2) For sterility testing: Twenty im-mediate containers, collected at regu-lar intervals throughout each fillingoperation.

(b)(1) Potency. Proceed as directed in§ 436.105 of this chapter, preparing thesample for assay as follows: Place anaccurately weighed representative por-tion of the ointment in a separatoryfunnel containing 50 milliliters of rea-gent-grade petroleum ether. Shakeuntil dissolved. Wash with four sepa-rate washings of a 4:1 mixture of meth-yl alcohol and distilled water. Combinethe washings and bring to volume withthe methyl alcohol-water solution in a

volumetric flask. Further dilute with0.1M potassium phosphate buffer, pH8.0 (solution 3), to the reference con-centration of 1.0 microgram of erythro-mycin base per milliliter (estimated).



[39 FR 19149, May 30, 1974, as amended at 49FR 5097, Feb. 10, 1984; 50 FR 19921, May 13,1985]

Subpart E [Reserved]

Subpart F—Dermatologic DosageForms

§ 452.510 Erythromycin dermatologicdosage forms.

§ 452.510a Erythromycin ointment.(a) Requirements for certification—(1)

Standards of identity, strength, quality,and purity. Erythromycin ointment iserythromycin in a suitable and harm-less ointment base. It may containsuitable preservatives. Each gram ofointment contains 20 milligrams oferythromycin. Its potency is satisfac-tory if it is not less than 90 percent andnot more than 125 percent of the num-ber of milligrams of erythromycin thatit is represented to contain. The mois-ture content is not more than 1.0 per-cent. The erythromycin used conformsto the standards prescribed by§ 452.10(a)(1) (i), (iii), (iv), (v), (vii), and(viii).







the batch: 10 packages, each containingnot less than 500 milligrams.


945

Food and Drug Administration, HHS § 452.510b


(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Place an accuratelyweighed representative portion of theointment in a separatory funnel con-taining 50 milliliters of reagent-gradepetroleum ether. Shake until dissolved.Wash with four separate washings of a4:1 mixture of methyl alcohol and dis-tilled water. Combine the washings andbring to volume with the methyl alco-hol-water solution in a volumetricflask. Further dilute with 0.1M potas-sium phosphate buffer, pH 8.0 (solution3), to the reference concentration of 1.0microgram of erythromycin base permilliliter (estimated).


[39 FR 19149, May 30, 1974, as amended at 49FR 5097, Feb. 10, 1984; 49 FR 47829, Dec. 7,1984; 50 FR 47214, Nov. 15, 1985]

§ 452.510b Erythromycin topical solu-tion.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin topical solu-tion contains in each milliliter 15.0 or20.0 milligrams of erythromycin. Itmay also contain one or more suitableand harmless solvents, surfactants,buffer substances, diluents, and per-fumes. Its potency is satisfactory if itis not less than 90 percent and notmore than 125 percent of the number ofmilligrams of erythromycin that it isrepresented to contain. If it contains15.0 milligrams of erythromycin permilliliter, its moisture content is notmore than 5.0 percent. If it contains20.0 milligrams of erythromycin permilliliter, its moisture content is notmore than 8.0 percent, except if it con-tains acetone, its moisture content isnot more than 2.0 percent. The erythro-mycin used conforms to the standardsprescribed by § 452.10(a)(1), exceptheavy metals.

(2) Packaging. In addition to the re-quirements of § 432.1 of this chapter, itmay either be dispensed on individ-ually packaged pledgets, each individ-ual pledget containing 0.8 milliliter of

erythromycin topical solution, or in ajar containing 60 pledgets. The jar con-tains 0.8 milliliter of erythromycintopical solution per pledget. Althoughthe pledgets in the jar are not individ-ually packaged, the drug is uniformlydistributed throughout the pledgets.The erythromycin topical solutionused on the pledgets contains 20 milli-grams of erythromycin per milliliter.







the batch: 10 packages, each containingapproximately 500 milligrams.


(b) Tests and methods of assay. If theerythromycin topical solution is dis-pensed on a pledget, express the con-tents of a representative number ofpledgets into a suitable container toobtain a volume of sample adequate toperform each assay described in para-graph (b)(1) and (2) of this section.

(1) Potency. Proceed as directed in§ 436.105 of this chapter, preparing thesample for assay as follows: Using asuitable hypodermic needle and sy-ringe, remove an accurately measuredrepresentative portion of the sampleand dilute with 0.1M potassium phos-phate buffer, pH 8.0 (solution 3), to ob-tain a stock solution of convenientconcentration. Further dilute an ali-quot of the stock solution with solu-tion 3 to the reference concentration of1.0 microgram of erythromycin baseper milliliter (estimated).

(2) Moisture. Proceed as directed in§ 436.201 of this chapter, except if the


946

21 CFR Ch. I (4–1–98 Edition)§ 452.510d

sample contains acetone, in lieu of Sol-vent A, use a mixture of pyridine andmethanol (1:1).

[46 FR 2995, Jan. 13, 1981, as amended at 48FR 51293, Nov. 8, 1983; 49 FR 374, Jan. 4, 1984;50 FR 1504, Jan. 11, 1985; 50 FR 19921, May 13,1985; 50 FR 20204, May 15, 1985; 54 FR 47352,Nov. 14, 1989; 54 FR 50472, Dec. 6, 1989]

§ 452.510d Erythromycin-benzoyl per-oxide topical gel.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin-benzoyl per-oxide topical gel is erythromycin pack-aged in combination with a suitableand harmless gel containing benzoylperoxide and one or more suitabledispersants, stabilizing agents, per-fumes, and wetting agents. When re-constituted as directed in the labeling,each gram contains 30 milligrams oferythromycin and 50 milligrams of ben-zoyl peroxide. The erythromycin con-tent is satisfactory if it contains notless than 90 percent and not more than125 percent of the number of milli-grams of erythromycin that it is rep-resented to contain. The benzoyl perox-ide content is satisfactory if it con-tains not less than 90 percent and notmore than 115 percent of the milli-grams of benzoyl peroxide that it isrepresented to contain. The erythro-mycin used conforms to the standardsprescribed by § 452.10(a)(1), except withrespect to heavy metals.





(b) The batch for erythromycin con-tent and benzoyl peroxide content.


(a) The erythromycin used in makingthe batch: 5 packages, each containingapproximately 100 milligrams.

(b) The batch: A minimum of 8 con-tainers.

(b) Tests and methods of assay—(1)Erythromycin content. Proceed as di-rected in § 436.105 of this chapter, pre-paring the sample for assay as follows:Reconstitute the sample as directed inthe labeling. Place an accuratelyweighed representative portion of theconstituted product into a high-speedglass blender jar containing 0.5 milli-liter of polysorbate 80 and sufficient0.1M potassium phosphate buffer, pH8.0 (solution 3), to obtain a stock solu-tion of convenient concentration.Blend for 3 to 5 minutes. Further dilutean aliquot of the stock solution withsolution 3 to the reference concentra-tion of 1.0 microgram of erythromycinbase per milliliter (estimated).

(2) Benzoyl peroxide content. Reconsti-tute the sample as directed in the la-beling. Place an accurately weightedrepresentative portion (about 2.5grams) of the constituted product intoa tared 250-milliliter glass-stopperedflask. Add 50 milliliters of glacial ace-tic acid and 20 milliliters of methylenechloride. Stopper and shake vigorouslyto disperse the gel. Add 1.0 milliliterphenylsulfide, swirl, stopper, and allowto stand at room temperature for 2minutes. Purge the flask with nitrogenfor 3 seconds. Add 5 milliliters forfreshly prepared saturated sodium io-dide solution, stopper, and swirl tomix. Let stand in the dark for 30 min-utes. Add 50 milliliters of previouslyboiled and cooled distilled water andtitrate the liberated iodine with 0.1Nsodium thiosulfate, adding starch T.S.near the endpoint. Perform a blank de-termination and correct the sampletiter. Each milliliter of 0.1N sodiumthiosulfate is equivalent to 12.11 milli-grams of benzoyl peroxide. Calculatethe benzoyl peroxide content as fol-lows:

Percentbenzoylperoxide

Normality of sodium

ght in grams=

××

Vuthiosulfate

Sample wei

12 11.

where:

Vu=Milliliters of sodium thiosulfate used inthe titration of the sample minus themilliliters of sodium thiosulfate used inthe titration of the sample blank.

[49 FR 47485, Dec. 5, 1984; 49 FR 49090, Dec. 18,1984; 49 FR 49449, Dec. 20, 1984, as amended at55 FR 11584, Mar. 29, 1990]


947


§ 452.510e Erythromycin topical gel.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin topical gel iserythromycin in a suitable and harm-less gel. Each gram contains 20 milli-grams of erythromycin. The erythro-mycin content is satisfactory if it con-tains not less than 90 percent and notmore than 125 percent of the number ofmilligrams of erythromycin that it isrepresented to contain. The erythro-mycin used conforms to the standardsprescribed by § 452.10(a)(1), except withrespect to heavy metals.


(3) Requests for certification; samples.In addition to complying with the re-quirements of § 431.1 of this chapter,each request shall contain:

(i) Results of tests and assays on:(A) The erythromycin used in mak-

ing the batch for potency, moisture,pH, residue on ignition, identity, andcrystallinity.

(B) The batch for erythromycin con-tent.


(A) The erythromycin used in mak-ing the batch: 5 packages, each con-taining approximately 100 milligrams.

(B) The batch: A minimum of 8 con-tainers.

(b) Tests and methods of assay; erythro-mycin content. Proceed as directed in§ 436.105 of this chapter, preparing thesample for assay as follows: Place ap-proximately 1 gram, accuratelyweighed, of the product into a high-speed glass blender jar containing 200milliliters of 0.5 percent (volume byvolume) polysorbate 80 in 0.1M potas-sium phosphate buffer, pH 8.0 (solution3), to obtain a stock solution of con-venient concentration. Blend for 3 to 5minutes. Further dilute an aliquot ofthe stock solution with solution 3 tothe reference concentration of 1.0microgram of erythromycin base permilliliter (estimated).

[53 FR 12415, Apr. 14, 1988; 53 FR 16837, May11, 1988]

Subpart G [Reserved]

Subpart H—Rectal Dosage Forms

§ 452.710 Erythromycin suppositories.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin suppositoriescontain in each suppository 125 milli-grams of erythromycin in a suitableand harmless base. The erythromycincontent is satisfactory if it is not lessthan 90 percent nor more than 120 per-cent of the number of milligrams oferythromycin that it is represented tocontain. The moisture content is notmore than 1.0 percent. The erythro-mycin used conforms to the standardsprescribed by § 452.10(a)(1), (i), (iii), (iv),(v), (vii), and (viii), except its moisturecontent is not more than 5.0 percent.







the batch: 10 packages, each containingnot less than 500 milligrams.

(b) The batch: A minimum of 30 sup-positories.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Blend a representa-tive number of suppositories for 3 to 5minutes in a high-speed glass blenderwith 200 milliliters of methyl alcohol.Add 300 milliliters of 0.1M potassiumphosphate buffer, pH 8.0 (solution 3),and blend again for 3 to 5 minutes. Re-move an aliquot and dilute with solu-tion 3 to the reference concentration of1.0 microgram of erythromycin baseper milliliter (estimated).


948

21 CFR Ch. I (4–1–98 Edition)§ 452.910



Subpart I [Reserved]

Subpart J—Certain Other DosageForms

§ 452.910 Erythromycin for prescrip-tion compounding.

(a) Requirements for certification—(1)Standards of identity, strength, quality,and purity. Erythromycin for prescrip-tion compounding is the odorless,white to grayish-white or slightly yel-low compound of a kind of erythro-mycin or a mixture of two or moresuch compounds. It is so purified anddried that:

(i) It contains not less than 850micrograms of erythromycin per milli-gram calculated on an anhydrous basis.

(ii) Its moisture content is not morethan 10 percent.

(iii) Its pH is not less than 8.0 normore than 10.5.


(v) It gives a positive identity testfor erythromycin.

(vi) It is crystalline.(2) Packaging. The immediate con-

tainer shall be a tight container as de-fined by the United States Pharma-copeia XXI. It shall be so sealed thatthe contents cannot be used withoutdestroying such seal. Each such con-tainer shall contain 10 grams, 25 grams,or 100 grams of erythromycin.

(3) Labeling. In addition to the re-quirements of § 432.5(a)(3) of this chap-ter, each package shall bear on its out-side wrapper or container and on theimmediate container the following:

(i) The statement ‘‘Caution: Federallaw prohibits dispensing without pre-scription.’’

(ii) The statement ‘‘Not sterile.’’(iii) The batch mark.(iv) The number of micrograms of

erythromycin activity in each milli-gram of erythromycin and the numberof grams of erythromycin in the imme-diate container.

(v) The statement ‘‘The potency ofthis drug cannot be assured for longer

than 90 days after the container is firstopened for compounding a prescrip-tion.’’

(vi) The statements ‘‘For use only inextemporaneous prescriptioncompounding. Not for manufacturinguse.’’


(i) Results of tests and assays on thebatch for potency, moisture, pH, resi-due on ignition, identity, and crys-tallinity.

(ii) Samples, if required by the Direc-tor, Center for Drug Evaluation andResearch: 10 packages, each containingnot less than 500 milligrams.

(b) Tests and methods of assay—(1) Po-tency. Proceed as directed in § 436.105 ofthis chapter, preparing the sample forassay as follows: Dissolve an accu-rately weighed sample in sufficientmethyl alcohol to obtain a concentra-tion of 10 milligrams of erythromycinbase per milliliter (estimated). Dilutethis solution further with sufficient0.1M potassium phosphate buffer, pH8.0 (solution 3), to obtain a stock solu-tion containing 1.0 milligram of eryth-romycin base per milliliter (esti-mated). Further dilute an aliquot ofthe stock solution with solution 3 tothe reference concentration of 1.0microgram of erythromycin base permilliliter (estimated).


(3) pH. Proceed as directed in § 436.202of this chapter, except standardize thepH meter with pH 7.0 and pH 10.0 buff-ers and prepare the sample as follows:Dissolve 200 milligrams of sample in 5milliliters of reagent grade methyl al-cohol. Add 95 milliliters of water andmix. Record the pH when an equi-librium value has been reached.


(5) Identity test. Proceed as directedin § 436.211 of this chapter, using thesample preparation method describedin paragraph (b)(3) of that section.


[51 FR 35213, Oct. 2, 1986, as amended at 55 FR11584, Mar. 29, 1990; 55 FR 25392, June 21, 1990]


part 452—macrolide antibiotic drugs · 911 food and drug administration, hhs pt. 452 (ii) samples...

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