STANDARD OPERATING PROCEDURE

TITLE : FINISHED PRODUCT QUALITY CONTROL PROTOCOLS FOR ALUMINUM HYDROXIDE AND MAGNESIUM HYDROXIDE SUSPENSION, USP

FUNCTION : REGULATORY AND QUALITY ASSURANCE DEPARTMENT

TABLE OF CONTENTS

1. PURPOSE ................................................................................................................. 2

2. SCOPE ...................................................................................................................... 3

3. DEFINITIONS ............................................................................................................ 4

4. MATERIALS AND EQUIPMENT.............................................................................. 5

5. ROLES AND RESPONSIBILITIES........................................................................... 6

6. PROCEDURES.......................................................................................................... 7

7. ACCEPTANCE CRITERIA........................................................................................ 12

8. REFERENCES........................................................................................................... 13

This document describes the quality control parameters and specifications for the product, Aluminum Hydroxide and Magnesium Hydroxide suspension, as stated by the United States Pharmacopoeia. The sample to be tested is Aluminum Hydroxide and Magnesium Hydroxide, 225 mg/ 200 mg/ 5 mL suspension, manufactured by Drugmaker’s Laboratories, Inc. It will be subjected to assay, deliverable volume test, particle size distribution test, sedimentation volume test, redispersibility, test for viscosity, pH and organoleptic evaluation. The Quality Assurance Department of Quales Philippines ensures that proper test procedures, equipment, standard operating procedures (SOPs) and current good manufacturing practices (cGMPs) are being followed during the Finished Product Quality Control (FPQC) of the drug product. 1. PURPOSE:

Generally, the Final Product Quality Control (FPQC) aims to determine if the finished drug product possesses appropriate quality properties based on the standards set by USP. For more systematic and efficient work, the company has set protocols for the quality control parameters and specifications for the drug.

1.1. For the Assay of Aluminum Hydroxide and Magnesium Hydroxide Suspension, the study aims

to: determine the strength or content of the active pharmaceutical ingredient in the dosage form; and determine whether the actual amount of active ingredient in the sample complies with its label claim.

1.2. For the Deliverable Volume Test, the study aims to: ensure that the volume of dosage form declared

on the label will be delivered by the product when transferred from the original container.

1.3. For the Particle Size Distribution Test, the study aims to: determine the division of different particle size of the product and distribution of the active ingredient in the drug product

1.4. For the Sedimentation Volume Test, the study aims to: determine the stability of the product and

efficiency of the suspending agent by measuring the extent of sedimentation

1.5. For the Redispersibility Test, the study aims to: determine whether the product is redispersible or

not since this affects the distribution of active ingredients in the drug product

1.6. For the Test for Viscosity, the study aims to: determine the resistance to flow exhibited by the product; and ensure its quality, stability and efficiency as viscosity greatly affects product performance.

1.7. For the Test for pH, the study aims to: determine the pH of the drug product, which affects the

effectiveness of the drug as an antacid.

1.8. For the Organoleptic Evaluation, the study aims to: determine the quality of the suspension through observing its physical appearance, including its packaging; and confirm if it still remains to be of high quality or it has visibly deteriorated.

2. SCOPE

2.1. The scope of this procedure is limited to the Aluminum Hydroxide and Magnesium Hydroxide

Suspension manufactured by Drugmaker’s Laboratories, Inc., which will be subjected under quality control parameters and specifications. These are to be conducted by and restricted to all the personnel of Quales Philippines at the Quality Assurance Laboratory of the College of Pharmacy, University of the Philippines Manila.

2.2. The procedure covers the assay, deliverable volume test, particle size distribution test, sedimentation volume test, redispersibility, test for viscosity, pH and organoleptic evaluation of the sample drug.

3. DEFINITIONS

3.1. Assay- test which determines the strength or content of the active pharmaceutical ingredient in

the dosage form; also called Content Test.

3.2. Deliverable volume- volume of dosage form declared on the label which will be delivered by the product when transferred from the original container; this test also ensures the accuracy and consistency of manufacturer-supplied products.

3.3. Particle Size Distribution- index indicating what sizes of particles are present in what proportions in the sample particle group to be measured

3.4. Sedimentation Volume- ratio of the equilibrium volume of the sediment, Vu, to the total volume, Vo of the suspension; this test gives only a qualitative idea about the sedimentation of the suspension.

3.5. Redispersibility- measure as to how readily the particles are resuspended after shaking thoroughly

3.6. Viscosity- an internal property of a fluid that offers resistance to flow.

4. MATERIALS AND EQUIPMENT

4.1. Assay 4.1.1. Buret 4.1.2. 125 mL Erlenmeyer Flask 4.1.3. Two 50 mL beakers 4.1.4. 250 mL beaker 4.1.5. 200 mL volumetric flask

4.1.6. Filter paper 4.1.7. Dropper

4.2. Deliverable Volume Test

4.2.1. 30 containers of Aluminum Hydroxide and Magnesium Hydroxide Suspension 4.2.2. 10 100-mL graduated cylinders

4.3. Particle Size Distribution Test

4.3.1. Microscope 4.3.2. Glass slides 4.3.3. Cover slips

4.4. Sedimentation Volume Test

4.4.1. 100-ml graduated cylinder

4.5. Redispersibility Test 4.5.1. 100-ml graduated cylinder

4.6. Test for Viscosity

4.6.1. Brookfield Dial Viscometer 4.6.2. 50-mL graduated cylinders

4.7. Test for pH

4.7.1. pH Meter

5. ROLES AND RESPONSIBILITIES

Name Position Signature

Leigh Don T. Villanueva Quality Assurance Head Charleen Joyce C. Usacdin Quality Assurance Personnel

Ann Lorraine U. Te Quality Control Head Maria Lourdes L. Jacinto Quality Control

TEST FOR VISCOSITY

Balde, Nikki Francine D. Quality Control

Reyes, Ton Agustine F. Quality Control

Asis, Janina Marie A. Quality Control

pH AND PARTICLE SIZE DISTRIBUTION

Yumol, Regene C. Quality Control

Demafiles, Shaynne Laurice A. Quality Control

Maniquis, B. Kim Leileeni D. Quality Control

Nieva, Kristel Keith N. Quality Control

ASSAY

Bacungan, Priscilla Nicole T. Quality Control

Legaspi, Donato D. Jr. Quality Control

Alcantara, Salve Alessandria B. Quality Control

Viva, Grace Kristin T. Quality Control

SEDIMENTATION VOLUME TEST AND ORGANOLEPTIC EVALUATION

Rivera, Darien John Q. Quality Control

Mappatao, Nikolai Thadues Q. Quality Control

DELIVERABLE VOLUME AND REDISPERSIBILITY

Magno, Daryl E. Quality Control

Tabud, Daryl G. Quality Control Olayan, Imma Coney P. Quality Control

6. PROCEDURE AND GUIDELINES

6.1. Aluminum Hydroxide Assay:

6.1.1. Assay Preparation

6.1.1.1. Transfer 26.0 mL of Oral Suspension, previously well shaken in its original

container to a 100 mL beaker.

6.1.1.2. Add 20 mL of water, stir, and slowly add 10 mL of hydrochloric acid.

6.1.1.3. Heat gently, if necessary, to aid solution, cool, and filter into a 200-mL volumetric

flask.

6.1.1.4. Wash the filter with water into the flask, add water to volume, and mix.

6.1.2. Assay Procedure

6.1.2.1. Pipet 10 mL of Assay preparation into a 250-mL in beaker then add 20 mL of

water.

6.1.2.2. Add, in the order named and with continuous stirring, 25.0 mL of 0.05 M Edetate

disodium titrant and 20 mL of acetic acid–ammonium acetate buffer TS.

6.1.2.3. Cool, add 50 mL of alcohol and 2 mL of dithizone TS, and mix,

6.1.2.4. Titrate with 0.05 M zinc sulfate VS until the color changes from green-violet to rose-

pink.

6.1.2.5. Perform a blank determination, substituting 10 mL of in the Assay preparation, and

make any necessary correction.

6.1.2.6. Each mL of 0.05 M Edetate disodium titrant consumed is equivalent to 3.900 mg of

Al(OH)3.

6.1.3. Sample Computations:

Aluminum Hydroxide

𝑤𝑡. (𝑔) = 𝑀𝑇 × 𝑉𝑇 ×𝑀𝑊𝑎𝑛𝑎𝑙𝑦𝑡𝑒

𝑓 × 1000

=0.05𝑀 × (25𝑚𝑙 − 10𝑚𝑙) ×78 𝑔/𝑚𝑜𝑙

𝑓1𝑋1000

=0.0585g Al(OH)3

0.0585𝑔

10𝑚𝐿=

𝑥

200𝑚𝐿

X= 1.1700g of Al(OH)3

1.1700𝑔

𝑥=

. 225𝑔 𝐴𝑙(𝑂𝐻)3

5𝑚𝐿 𝑠𝑢𝑠𝑝

X= 26.00mL of Oral suspension

Assay Computation

𝒘𝒕 𝒐𝒇 𝑨𝒍(𝑶𝑯)𝟑𝒑𝒆𝒓 𝟐𝟓 𝒎𝒍 =[𝑀𝐸𝐷𝑇𝐴 𝑥 𝑁𝐹 𝑥 (𝑉𝐸𝐷𝑇𝐴 − 𝑉𝑏𝑙𝑎𝑛𝑘)] − [𝑀𝑏𝑎𝑐𝑘 𝑥 𝑁𝐹 𝑥 (𝑉𝑏𝑎𝑐𝑘 − 𝑉𝑏𝑙𝑎𝑛𝑘)] 𝑥

𝑀𝑊 𝐴𝑙(𝑂𝐻)3𝑓 𝑥 1000

𝟏𝟎𝒎𝑳𝒙 𝟐𝟎𝟎𝒎𝑳

Convert to equivalent of 5 mL of Oral Suspension

Then compute for % Label Claim

Example:

𝒘𝒕 𝒐𝒇 𝑨𝒍(𝑶𝑯)𝟑𝒑𝒆𝒓 𝟐𝟓 𝒎𝒍 =[0.05𝑀 𝑥 1.001 𝑥 (25.00𝑚𝐿 − 1.00𝑚𝐿)] − [0.05𝑀 𝑥 1.002 𝑥 (10.00𝑚𝐿 − 1.00𝑚𝐿)] 𝑥

78𝑔/𝑚𝑜𝑙1 𝑥 1000

𝟏𝟎𝒎𝑳𝒙 𝟐𝟎𝟎𝒎𝑳

= 1.1704 g / 25 mL

= 0.234 g / 5mL

Compute for the % Labelled Claim

%𝐿𝐶 =𝑎𝑐𝑡𝑢𝑎𝑙

𝑡ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑋100

%𝐿𝐶 =

0.234𝑔5𝑚𝑙

0.225𝑔5𝑚𝑙

𝑋100

=104.04%

6.2. Magnesium Hydroxide Assay

6.2.1. Assay Preparation

6.2.1.1. Transfer 26.0 mL of Oral Suspension, previously well shaken in its original

container to a 100 mL beaker.

6.2.1.2. Add 20 mL of water, stir, and slowly add 10 mL of hydrochloric acid.

6.2.1.3. Heat gently, if necessary, to aid solution, cool, and filter into a 200-mL volumetric

flask.

6.2.2. Assay Procedure

6.2.2.1. Pipet 8.00 mL of Assay preparation, into a 400-mL beaker.

6.2.2.2. Add 200 mL of water and 20 mL of triethanolamine, and stir.

6.2.2.3. Add 10 mL of ammonia-ammonium chloride buffer TS and 3 drops of an

eriochrome black indicator solution.

6.2.2.4. Eriochrome black indicator solution is prepared by dissolving 200 mg of eriochrome

black T in a mixture of 15 mL of triethanolamine and 5 mL of dehydrated alcohol,

and mix.

6.2.2.5. Cool the solution to between 3° and 4° by immersion of beaker in an ice bath, then

remove.

6.2.2.6. Titrate with 0.05 M edetate disodium VS to a blue endpoint.

6.2.2.7. Perform a blank determination, substituting 10 mL of water for the Assay

preparation make any necessary correction.

6.2.2.8. Each mL of 0.05 M edetate disodium consumed is equivalent to 2.916 mg of

Mg(OH)2.

6.2.3. Sample Computation

Magnesium Hydroxide

26.00 𝑚𝐿

𝑋 𝑚𝑔=

5 𝑚𝐿

200𝑚𝑔

X= 1.040 g of Mg(OH)2

MEDTA = 0.05 M Nf EDTA = 1.001 Volume of EDTA = 25.00 mL

MW Al(OH)3 = 78g/mol VBlank = 1.00 mL

MZnSO4 = 0.05 M Nf ZnSO4 = 1.002 Volume of ZnSO4 = 10.00 mL

F = 1

1.040𝑔

200 𝑚𝐿=

0.040𝑔 𝑀𝑔(𝑂𝐻)2

𝑥 𝑚𝐿

X= 8.00mL of Oral suspension

Assay Computation

𝑤 𝑜𝑓 𝑀𝑔(𝑂𝐻)2 𝑖𝑛 𝑎𝑠𝑠𝑎𝑦 𝑝𝑟𝑒𝑝 = 𝑀𝐸𝐷𝑇𝐴 𝑥 (𝑉𝑎𝑐𝑡𝑢𝑎𝑙 − 𝑉𝑏𝑙𝑎𝑛𝑘) 𝑥

58.32 𝑔/𝑚𝑜𝑙1000

8 𝑚𝑙 𝑥 200𝑚𝐿

Convert to equivalent of 5 mL of Oral Suspension

Then compute for % Label Claim

Example:

𝑤 𝑜𝑓 𝑀𝑔(𝑂𝐻)2 𝑖𝑛 𝑎𝑠𝑠𝑎𝑦 𝑝𝑟𝑒𝑝 = 0.05𝑀 𝑥 (15.00 𝑚𝐿 − 1.00 𝑚𝐿) 𝑥

58.32 𝑔/𝑚𝑜𝑙1000

8 𝑚𝑙 𝑥 200𝑚𝐿

= 1.0206 g / 25 mL

= 0.2041 g / 5mL

Compute for the % Labelled Claim

%𝐿𝐶 =𝑎𝑐𝑡𝑢𝑎𝑙

𝑡ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑋100

%𝐿𝐶 =

0.2041 𝑔5𝑚𝑙

0.200𝑔5𝑚𝑙

𝑋100

=102.06 %

6.3. Deliverable Volume Test

6.3.1. Obtain not fewer than 30 containers of Aluminum Hydroxide and Magnesium Hydroxide

Suspension.

6.3.2. Shake the contents of 10 containers individually.

6.3.3. Gently pour the contents of each container into separate dry graduated cylinders of a

capacity not exceeding two and half times the volume to be measured and calibrated “to

contain”. Avoid formation of air bubbles.

6.3.4. Allow each container to drain for a period not to exceed 30 minutes.

6.3.5. Measure the volume of each mixture as it becomes free from bubbles.

6.4. Particle Size Distribution Test

6.4.1. Mount sample on a slide and place on a mechanical stage

6.4.2. Fit a micrometer in the eyepiece of the microscope

6.4.3. Count and measure the particles seen

6.4.4. Create a frequency distribution curve.

6.5. Sedimentation Volume Test

MEDTA = 0.05 M Nf EDTA = 1.001 Volume of EDTA = 15.00 mL

MW Al(OH)3 = 78g/mol VBlank = 1.00 mL

6.5.1. Shake the suspension vigorously, making sure all of the particles are suspended

uniformly.

6.5.2. Immediately pour the suspension into a 100-ml graduated cylinder.

6.5.3. Take note of the total volume (Vo) of the suspension.

6.5.4. Allow the suspension to sit undisturbed for 24 hours.

6.5.5. Then, determine and record the final volume (Vu) of the sediment.

6.5.6. Calculate the sedimentation volume (F) using this formula: 𝐹 = Vu / VO

6.6. Redispersibility Test

6.6.1. Place reconstituted suspension in 100 mL graduated cylinder.

6.6.2. Let suspension stand for 24 hours.

6.6.3. Invert graduated cylinder and count number of inversions required to resuspend

particles.

6.6.3.1.1. Each inversion must be done for 1 second.

6.6.3.1.1.1. Record time required to achieve resuspension.

6.7. Test for Viscosity

6.7.1. Place the sample in a 50-mL graduated cylinder.

6.7.2. Attach the appropriate spindle to the viscometer.

6.7.3. Immerse the spindle into the sample so that its annular groove is at the surface level of

the sample. Ensure that the spindle is in the center of the container opening.

6.7.4. Make sure to place the spindle guard to protect the torsion spring.

6.7.5. Place the instrument in its slowest fixed speed.

6.7.6. Align the pointer to coincide with the zero of the scale.

6.7.7. Depress the clutch of the instrument and turn the unit on.

6.7.8. Release slowly the clutch to allow the dial to rotate until the pointer stabilizes at a

fixed

position on the dial.

6.7.9. Depress the clutch again and turn the unit off, with the pointer clearly visible within

the

dial window.

6.7.10. Record the reading at which the pointer coincide. Refer to the Factor-Finder

supplied/found with the viscometer for the viscosity of the sample.

6.7.11. Repeat steps 4 to 5 but in the next higher speed.

6.7.12. Continue until the pointer moves more than the maximum reading.

6.7.13. Without letting the system to reform, repeat steps 4 to 5 but this time from the last higher

speed to the lowest speed.

6.7.14. Plot the shear rate (rpm) vs. shear stress (dial reading).

6.7.15. Determine the yield value by multiplying the dial reading to the appropriate factor for the

spindle and speed use, provided with the viscometer.

6.7.16. Sample Computation

Given:

Spindle no. 3, Speed= 0.3

Dial Reading= 2

Factor= 4000

To get viscosity:

Dial Reading x Factor = Viscosity

2 x 4000 = 8000 centipoise (cps)

6.8. Test for pH

6.8.1. Use pH meter to determine the pH of the suspension.

6.9. Organoleptic Evaluation

The suspension is observed for its physical characteristics, including its packaging.

7. ACCEPTANCE CRITERIA

7.1. Assay

It contains the equivalent of not less than 90.0 percent and not more than 110.0 percent of the

labeled amounts of aluminum hydroxide [Al(OH)3] and magnesium hydroxide [Mg(OH)2].

7.2. Deliverable Volume Test

The average volume of liquid obtained from the 10 containers is not less than 100% and the volume

of no container is less than 95% of the volume declared in the labeling. If A, the average volume is

less than 100% of that declared in the labeling, but the volume of no container is less than 95% of

the labeled amount, or if B, the average volume is not less than 100% and the volume of not more

than 1 container is less than 95% but is not less than 90% of the labeled volume, perform the test

on 20 additional containers. The average volume of liquid obtained from the 30 containers is not

less than 100% of the volume declared in the labeling; and the volume of liquid obtained from not

more than 1 of the 30 containers is less than 95%, but not less than 90% of that declared in the

labeling.

7.3. Particle Size Distribution Test

A normal distribution curve must be observed

7.4. Sedimentation Volume Test

The value of F normally lies between 0 to 1 for any pharmaceutical suspension.

7.5. Redispersibility Test

Uniform dispersion; evaluated qualitatively as constant percentage of inversion of the suspension

7.6. Test for Viscosity

The suspension exhibits pseudoplastic behavior. 7.7. Test for pH

pH ranges from 7.0 to 8.6.

7.8. Organoleptic Evaluation

Milky white suspension

8. REFERENCES

8.1. Gennaro, A., 1995. Remington: The Science and Practice of Pharmacy, 19th ed. Mack

Publishing.

8.2. Kulshreshtha, A.K., Singh, O.N., Wall, G.M., 2010. Pharmaceutical Suspensions: From

Formulation Development to Manufacturing. New York: Springer, 53.

8.3. Singh, Y., Sinko, P.J., 2011. Martin’s Physical Pharmacy and Pharmaceutical Sciences.

Philadelphia: Lippincott Williams & Wilkins, 442-451

8.4. United States Pharmacopoeial Convention Inc., 2011. The United States Pharmacopoeial

Convention 33rd Revision and the National Formulary 28th Edition (e-book) Rockville

Md: USPCI.