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

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

Subpart I [Reserved]

Subpart J-Certain Other Dosage Forms

§ 452.910 Erythromycin for prescription compounding.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Erythromycin for prescription compounding is the odorless, white to grayish-white or slightly yellow compound of a kind of erythromycin or a mixture of two or more such compounds. It is so purified and dried that:

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

(ii) Its moisture content is not more than 10 percent.

(iii) Its pH is not less than 8.0 nor more than 10.5.

(iv) Its residue on ignition is not more than 2.0 percent.

(v) It gives a positive identity test for erythromycin.

(vi) It is crystalline.

(2) Packaging. The immediate container shall be a tight container as defined by the United States Pharmacopeia XXI. It shall be so sealed that the contents cannot be used without destroying such seal. Each such container shall contain 10 grams, 25 grams, or 100 grams of erythromycin.

(3) Labeling. In addition to the requirements of § 432.5(a)(3) of this chapter, each package shall bear on its outside wrapper or container and on the immediate container the following:

(i) The statement "Caution: Federal law prohibits dispensing without prescription."

(ii) The statement "Not sterile." (iii) The batch mark.

(iv) The number of micrograms of erythromycin activity in each milligram of erythromycin and the number of grams of erythromycin in the immediate container.

(v) The statement "The potency of this drug cannot be assured for longer

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

(i) Results of tests and assays on the batch for potency, moisture, pH, residue on ignition, identity, and crystallinity.

(ii) Samples, if required by the Director, Center for Drug Evaluation and Research: 10 packages, each containing not less than 500 milligrams.

(b) Tests and methods of assay—(1) Potency. Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Dissolve an accurately weighed sample in sufficient methyl alcohol to obtain a concentration of 10 milligrams of erythromycin base per milliliter (estimated). Dilute this solution further with sufficient 0.1M potassium phosphate buffer, pH 8.0 (solution 3), to obtain a stock solution containing 1.0 milligram of erythromycin base per milliliter (estimated). Further dilute an aliquot of the stock solution with solution 3 to the reference concentration of 1.0 microgram of erythromycin base per milliliter (estimated).

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

(3) pH. Proceed as directed in §436.202 of this chapter, except standardize the pH meter with pH 7.0 and pH 10.0 buffers and prepare the sample as follows: Dissolve 200 milligrams of sample in 5 milliliters of reagent grade methyl alcohol. Add 95 milliliters of water and mix. Record the pH when an equilibrium value has been reached.

(4) Residue on ignition. Proceed as directed in § 436.207(a) of this chapter.

(5) Identity test. Proceed as directed in § 436.211 of this chapter, using the sample preparation method described in paragraph (b)(3) of that section.

(6) Crystallinity. Proceed as directed in § 436.203(a) of this chapter.

[51 FR 35213, Oct. 2, 1986, as amended at 55 FR 11584, Mar. 29, 1990; 55 FR 25392, June 21, 1990]

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(ii) Its microbiological activity is not less than 800 micrograms of clindamycin per milligram.

(iii) [Reserved]

(iv) Its moisture content is not less than 3.0 percent and not more than 6.0 percent.

(v) Its pH in an aqueous solution containing 100 milligrams per milliliter is not less than 3.0 and not more than 5.5. (vi) It is crystalline.

(vii) It passes the identity test for clindamycin hydrochloride hydrate.

(2) Labeling. It shall be labeled in accordance with the requirements of § 432.5(b) of this chapter.

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

(i) Results of tests and assays on the batch for clindamycin content, microbiological activity, moisture, pH, crystallinity, and identity.

(ii) Samples required: 10 packages, each containing approximately 300 milligrams.

activity

(b) Tests and methods of assay--(1) Clindamycin content (vapor phase chromatography). Proceed as directed in § 436.302 of this chapter. (2) Microbiological (microbiological agar diffusion assay.) Proceed as directed in §436.105 of this chapter, preparing the sample for assay as follows: Dissolve an accurately weighed sample in sufficient sterile distilled water to give a stock solution of convenient concentration. Further dilute the stock solution with 0.1M potassium phosphate buffer, pH 8.0 (solution 3), to the reference concentration of 1.0 microgram of clindamycin per milliliter (estimated).

(3) [Reserved]

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

(5) pH. Proceed as directed in § 436.202 of this chapter, using an aqueous solution containing 100 milligrams per milliliter.

(6) Crystallinity. Proceed as directed in § 436.203 of this chapter.

(7) Identity. Proceed as directed in § 436.211 of this chapter, using the sample preparation method described in paragraph (b)(2) of that section.

[39 FR 19161, May 30, 1974, as amended at 50 FR 19921, May 13, 1985]

§ 453.21 Clindamycin palmitate hydrochloride.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Clindamycin palmitate hydrochloride is the white to off-white amorphous powder of the hydrochloride salt of the palmitic acid ester of clindamycin. It is freely soluble in water, ethanol, chloroform, and ether. It is so purified and dried that:

(i) It contains not less than 540 micrograms of clindamycin per milligram.

(ii) [Reserved]

(iii) Its moisture content is not more than 3.0 percent.

(iv) Its pH in an aqueous solution containing 10 milligrams per milliliter is not less than 2.8 and not more than 3.8.

(v) It passes the identity test for clindamycin palmitate hydrochloride. (2) Labeling. It shall be labeled in accordance with the requirements of § 432.5 of this chapter.

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

(i) Results of tests and assays on the batch for clindamycin content, moisture, pH, and identity.

(ii) Samples required: 10 packages, nine containing not less than 300 milligrams and one package containing not less than 2 grams.

(b) Tests and methods of assay-(1) Clindamycin content. Proceed as directed in § 436.303 of this chapter.

(2) [Reserved]

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

(4) pH. Proceed as directed in § 436.202 of this chapter, using an aqueous solution containing 10 milligrams per milliliter.

(5) Identity. Proceed as directed in § 436.211 of this chapter, using the sample preparation method described in paragraph (b)(2) of that section.

[39 FR 19161, May 30, 1974, as amended at 50 FR 19921, May 13, 1985]

§ 453.22 Clindamycin phosphate.

(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Clindamycin phosphate is a water-soluble ester of clindamycin and

phosphoric acid. It occurs as a white to off-white powder. It is so purified and dried that:

(i) Its clindamycin content is not less than 758 micrograms of clindamycin per milligram calculated on an anhydrous basis.

(ii) Its microbiological activity is not less than 758 micrograms of clindamycin per milligram calculated on an anhydrous basis. (iii) [Reserved]

(iv) Its moisture content is not more than 6.0 percent.

(v) Its pH in an aqueous solution containing 10 milligrams per milliliter is not less than 3.5 and not more than 4.5. (vi) It is crystalline.

(vii) It passes the identity test for clindamycin phosphate.

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

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

(i) Results of tests and assays on the batch for clindamycin content, microbiological activity, moisture, pH, crystallinity, and identity.

(ii) Samples required: 10 packages, nine containing approximately 300 milligrams and one containing 1.5 grams.

(b) Tests and methods of assay-(1) Clindamycin content (vapor phase chromatography). Proceed as directed in § 436.304 of this chapter.

(2) Microbiological activity (microbiological agar diffusion assay). Proceed as directed in §436.105 of this chapter, preparing the sample for assay as follows: Accurately weigh approximately 12 milligrams of the clindamycin phosphate sample into a 50-milliliter glassstoppered centrifuge tube. Pipet 25 milliliters of the pH 9.0 borate buffer into the centrifuge tube. Add 10 milliliters of chloroform and shake vigorously for 15 minutes. Centrifuge the resulting mixture and pipet a 20-milliliter aliquot of the aqueous phase into a 35milliliter centrifuge tube. Add a weighed amount of intestinal alkaline phosphatase equivalent to 50 units of

activity1 and allow the solution to stand until the enzyme has completely dissolved. Place the tube into a water bath at 37° C ±2° C for 2.5 hours. After the 2.5-hours hydrolysis, allow the solution to cool. Further dilute an aliquot of the solution with 0.1M potassium phosphate buffer, pH 8.0 (solution 3), to the reference concentration of 1.0 microgram of clindamycin per milliliter (estimated).

(3) [Reserved]

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

(5) pH. Proceed as directed in § 436.202 of this chapter, using an aqueous solution containing 10 milligrams per milliliter.

(6) Crystallinity. Proceed as directed in § 436.203(a) of this chapter.

(7) Identity. Proceed as directed in § 436.211 of this chapter, using the sample preparation method described in paragraph (b)(2) of that section, except dry the sample for 2 hours at 100° C and allow to equilibrate with the atmosphere for 1 hour.

[46 FR 2996, Jan. 13, 1981, as amended at 50 FR 19921, May 13, 1985]

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(a) Requirements for certification—(1) Standards of identity, strength, quality, and purity. Sterile clindamycin phosphate is a water-soluble ester of clindamycin and phosphoric acid. It occurs as a white to off-white powder. It is so purified and dried that:

(1) Its clindamycin content is not less than 758 micrograms of clindamycin per milligram calculated on an anhydrous basis.

(ii) Its microbiological activity is not less than 758 micrograms of clindamycin per milligram calculated on an anhydrous basis.

(iii) It is sterile.

(iv) It is nonpyrogenic. (v) [Reserved]

(vi) It contains no depressor substances.

(vii) Its moisture content is not more than 6 percent.

1 Defined such that 50 units hydrolyzes at least 20 micromoles of a clindamycin phosphate authentic sample under the assay conditions described in this section.

(viii) Its pH in an aqueous solution containing 10 milligrams per milliliter is not less than 3.5 and not more than 4.5.

(ix) It is crystalline.

(x) It passes the identity test for clindamycin phosphate.

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

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

(1) Results of tests and assays on the batch for clindamycin content, microbiological activity, sterility, pyrogens, depressor substances, moisture, pH, crystallinity, and identity.

(ii) Samples required:

(a) For all tests except sterility: 10 packages, nine containing approximately 300 milligrams and one containing 1.5 grams.

(b) For sterility testing: 20 packages, each containing approximately 300 milligrams.

activity

(b) Tests and methods of assay-(1) Clindamycin content (vapor phase chromatography). Proceed as directed in § 436.304 of this chapter. (2) Microbiological (microbiological agar diffusion assay). Proceed as directed in § 436.105 of this chapter, preparing the sample for assay as follows: Accurately weigh approximately 12 milligrams of the clindamycin phosphate sample into a 50-milliliter glass-stoppered centrifuge tube. Pipet 25 milliliters of the pH 9.0 borate buffer into the centrifuge tube. Add 10 milliliters of chloroform and shake vigorously for 15 minutes. Centrifuge the resulting mixture and pipet a 20-milliliter aliquot of the aqueous phase into a 35-milliliter centrifuge tube. Add a weighed amount of intestinal alkaline phosphatase equivalent to 50 units of activity1 and allow the solution to stand until the enzyme has completely dissolved. Place the tube into a water bath at 37° C.±2° C. for 2.5 hours. After the 2.5-hour hydrolysis, allow the solution to cool. Further dilute an aliquot of the solution with

1 Defined such that 50 units hydrolyzes at least 20 micromoles of a clindamycin phosphate authentic sample under the assay conditions described in this section.

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0.1M potassium phosphate buffer, pH 8.0 (solution 3), to the reference concentration of 1.0 microgram of clindamycin per milliliter (estimated).

(3) Sterility. Proceed as directed in § 436.20 of this chapter, using the method described in paragraph (e)(1) of that section.

(4) Pyrogens. Proceed as directed in § 436.32(a) of this chapter, using a solution containing 24 milligrams of clindamycin per milliliter.

(5) [Reserved]

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

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

(8) pH. Proceed as directed in §436.202 of this chapter, using an aqueous solution containing 10 milligrams per milliliter.

(9) Crystallinity. Proceed as directed in § 436.203(a) of this chapter.

(10) Identity. Proceed as directed in § 436.211 of this chapter, using the sample preparation method described in paragraph (b)(2) of that section, except dry the sample for 2 hours at 100° C. and allow to equilibrate with the atmosphere for 1 hour.

[39 FR 19161, May 30, 1974, as amended at 46 FR 60568, Dec. 11, 1981; 50 FR 19921, May 13, 1985]

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(vi) It passes the infrared identity test.

(vii) Its content of lincomycin B is not more than 5 percent.

(viii) It passes the identity test if the elution pattern of the lincomycin sample compares quantitatively to that of the lincomycin working standard under identical conditions of gas liquid chromatography.

(ix) It is crystalline.

(2) Labeling. It shall be labeled in accordance with the requirements of § 432.5(b) of this chapter.

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

(i) Results of tests and assays on the batch for potency, moisture, pH, specific rotation, infrared absorption spectrum, lincomycin B content, crystallinity, and identity.

(ii) Samples of the batch: 10 packages, each containing approximately 300 milligrams.

(b) Tests and methods of assay—(1) Potency. Use either of the following methods; however, the results obtained from the gas liquid chromatography assay shall be conclusive.

(i) Microbiological turbidimetric assay. Proceed as directed in § 436.106 of this chapter, preparing the sample for assay as follows: Dissolve an accurately weighed sample in sufficient sterile distilled water to obtain a stock solution of convenient concentration. Further dilute an aliquot of the stock solution with sterile distilled water to the reference concentration of 0.5 microgram of lincomycin per milliliter (estimated).

(ii) Gas liquid chromatography assay. Proceed as directed in § 436.306 of this chapter.

(2) [Reserved]

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

(4) pH. Proceed as directed in § 436.202 of this chapter, using an aqueous solution containing 100 milligrams per milliliter.

(5) Specific rotation. Accurately weigh 500 milligrams of lincomycin hydrochloride monohydrate in a 25-milliliter, glass stoppered volumetric flask and fill to volume with distilled water. Proceed as directed in § 436.210 of this

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