This document discusses various quality control tests for semisolid products like lidocaine ointment. It describes tests such as infrared absorption, assay testing using HPLC, uniformity of dosage, preservative effectiveness testing, pH testing, and viscosity testing. The infrared absorption test verifies the identity of lidocaine in the ointment. The assay test quantifies the amount of lidocaine using HPLC. Tests like uniformity of dosage and preservative effectiveness ensure consistency and prevent microbial growth.

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2. 2

3. Quality control tests of
semisolid products
Dr.Maryam kazemi
PhD student of pharmaceutics
Shiraz university of medical sciences
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4. Lidocaine Ointment
• A. Infrared A bsorption
Sample: Stir a quantity of Ointment, equivalent to
300 mg of lidocaine, with 20 mL of water, transfer to a
separator, and extract with two 30-mL portions of solvent
hexane. Wash the combined hexane extracts with
10 mL of water, evaporate with the aid of a current of
warm air, and dry tne residue in vacuum over silica gel
for 24 h.
Acceptance criteria: The crystalline precipitate so obtained
meets the requirements.
R B. The retention time of the major peak of the Sample
solution corresponds to that of the Standard solution, as
obtained in the Assay.
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5. Lidocaine OintmentASSAY
• Procedure
Solution A: 0.1% phosphoric acid, prepared by adding
1.0 mL of 85% phosphoric acid to 1 L of water.
Solution B: Acetonitrile
Diluent: Acetonitrile and Solution A (1:1)
System suitability solution: 0.1 mg/mL of USP Lidocaine
RS and 0.04 mg/mL of USP Ropivacaine Related
Compound A RS in Diluent
[Note—USP Ropivacaine Related Compound A RS is
2 , 6 -dimethylaniline hydrochloride.]
Standard solution: 0.1 mg/mL of USP Lidocaine RS in
Diluent
Sample solution: Nominally 0.1 mg/mL of lidocaine in
Diluent from a portion of Ointment. Sonicate the solution
for about 5 min.
Chromatographic system
(See Chromatography (621), System Suitability.)
Mode: LC
Detector: UV 210 nm
Column: 4.6-mm x 15-cm; 5-jjjti packing L1
Flow rate: 0.8 mL/min
Injection volume: 5 jiL
System suitability
Samples: System suitability solution and Standard
solution
[Note—The relative retention times for 2,6-dimethylaniline 5

6. .
and lidocaine are about 0.93 and 1.0,
respectively.]
Suitability requirements
Tailing factor: NMT 1.5 for the lidocaine peak, System
suitability solution
Relative standard deviation: NMT 2.0%, Standard
solution
Resolution: NLT 1.8 between lidocaine and 2,6-
dimethylaniline, System suitability solution
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of the labeled amount of lidocaine
(C14H22N2O) in the portion of Ointment taken:
Result = (ru//s) x (Cs/Cu) x 100
ru = peak response from the Sample solution
rs = peak response from the Standard solution
Q = concentration of USP Lidocaine RS in the
Standard solution (mg/mL)
Cu = nominal concentration of lidocaine in the
Sample solution (mg/mL)
Acceptance criteria: 95.0%-105.0%
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7. Liquid or Semi-Solid Dosage Forms
Assay 10 units individually using an appropriate
analytical method. Carry out the assay on the
amount of well-mixed material
that is removed from an individual container in
conditions of normal use, and express the results
as delivered dose. Calculate
the acceptance value (see Table 2)
Uniformity of dosage form
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8. • Calculation of Acceptance Value
• Calculate the acceptance value by the
formula:
• |M - x| + ks
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9. Solid, Semi-Solid, and Liquid Dosage Forms
The requirements for dosage uniformity are met if the
acceptance value of the first 10 dosage units is less
than or equal to
L1%. If the acceptance value is > L1%, test the next 20
units, and calculate the acceptance value. The
requirements are met if
the final acceptance value of the 30 dosage units is <
LI %, and no individual content of ‘any, dosage unit is
less than [1 -
(0.01)(L2)]M nor more than [1 + (0.01)(L2)]M ‘ as
specified, in the Calculation of Acceptance Value
under Content Uniformity or
under *Weight4 Variation. Unless otherwise specified,
LI is 15.0 and L2 is 25.
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10. SPECIFIC TESTS
• Microbial Enumeration tests and Tests
for Specified Microorganisms: It meets the
requirements of the tests for absence of
Staphylococcus aureus and Pseudomonas
aeruginosa.
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11. Antioxidant content:
If antioxidants are present in the drug product,
tests of their content should be established unless
oxidative degradation can be detected by another
test method such as impurity testing. Acceptance
criteria for antioxidant
content should be established. They should be
based on the levels of antioxidant necessary to
maintain the product's stability
at all stages throughout its proposed usage and
shelf life.
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12. Preservative effectiveness test
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13. Table 1. Compendial product categories
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14. • Candida albicans (ATCC No. 10231)
• Aspergillus niger (ATCC No. 16404)
• Escherichia coli (ATCC No. 8739)
• Pseudomonas aeruginosa (ATCC No.9027)
• Estaphylococcus aureus (ATCC No. 6538)
Test organisms
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15. • All the media used in this test must be tested
for growth promotion
Media
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16. Table 2. Culture conditions for inoculum
preparations
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17. • Category 1
Table 3. Criteria for antimicrobial effectiveness
test
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18. • Category 2
Table 4. Criteria for antimicrobial effectiveness
test
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19. • Category 3
Table 5. Criteria for antimicrobial effectiveness
test
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20. • Category 4
Table 6. Criteria for antimicrobial effectiveness
test
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21. pH:
When applicable, topically applied drug products
should be tested for pH at the time of batch
release and at designated
stability time points for batch-to-batch
monitoring. Because some topically applied drug
products contain very limited
quantities of water or aqueous phase, pH
measurements may not always be warranted. This
test is generally formulation dependent.
Therefore, it is not included in the compendial
drug product monograph but is part of the
manufacturer's specification
for the drug product.
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22. Particle size:
The particle size of the active drug substance(s) in topically applied
drug products is usually determined and
controlled at the formulation development stage. However, topically
applied drug products should be examined for evidence
of particle size alteration (i.e., appearance of particles; changes in
particle form, size, shape, habit, or aggregation) of the active
drug substance that may occur during the course of product
processing and storage. Such examinations should be conducted
at the time of batch release and at designated stability test time
points for batch-to-batch monitoring because changes that
are visually (macro- and microscopically) observable would likely
compromise the integrity and/or performance of the drug
product. These types of tests are generally formulation dependent.
Therefore, such tests are not included in compendial monographs
but are part of the manufacturer specification for the drug product.
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23. Water content:
Method la (Direct Titration)
The titrimetric determination of water is based upon the quantitative
reaction of water with an anhydrous solution
of sulfur dioxide and iodine in the presence of a buffer that reacts with
hydrogen ions.
Reagent—Prepare the Karl Fischer Reagent as follows. Add 125 g of
iodine to a solution containing 670 mL of methanol
and 170 mL of pyridine, and cool. Place 100 mL of pyridine in a 250-mL
graduated cylinder, and, keeping the pyridine cold in
an ice bath, pass in dry sulfur dioxide until the volume reaches 200
mL. Slowly add this solution, with shaking, to the cooled
iodine mixture. Shake to dissolve the iodine, transfer the solution to
the apparatus, and allow the solution to stand overnight before
standardizing. One mL of this solution when freshly prepared is
equivalent to approximately 5 mg of water, but it deteriorates
gradually; therefore, standardize it within 1 h before use, or daily if in
continuous use. Protect from light while in use.
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24. Method lb (Residual Titration)
Principle—See the information given in the section
Principle under Method la. In the residual titration,
excess Reagent is added to the test specimen,
sufficient time is allowed for the reaction to reach
completion, and the unconsumed Reagent is
titrated with a standard solution of water in a solvent
such as methanol. The residual titration procedure is
applicable generally and avoids the difficulties that
may be encountered in the direct titration of
substances from which the bound water is released
slowly.
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25. Method lc (Coulometric Titration)
Principle—The Karl Fischer reaction is used in the coulometric
determination of water. Iodine, however, is not added in the
form of a volumetric solution but is produced in an iodide-containing
solution by anodic oxidation. The reaction cell usually
consists of a large anode compartment and a small cathode
compartment that are separated by a diaphragm. Other suitable
types of reaction cells (e.g., without diaphragms) may also be used.
Each compartment has a platinum electrode that conducts
current through the cell. Iodine, which is produced at the anode
electrode, immediately reacts with water present in the compartment.
When all the water has been consumed, an excess of iodine occurs,
which usually is detected electrometrically, thus
indicating the endpoint. Moisture is eliminated from the system by
pre-electrolysis. Changing the Karl Fischer solution after
each determination is not necessary because individual
determinations can be carried out in succession in the same reagent
solution.
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26. Test Preparation—Where the specimen is a
soluble solid, an appropriate quantity, accurately
weighed, may be dissolved in anhydrous methanol
or other suitable solvents. Where the specimen is
an insoluble solid, an appropriate quantity,
accurately weighed, may be extracted using a
suitable anhydrous solvent, and may be injected
into the anolyte solution. Alternatively, an
evaporation technique may be used in which
water is released and evaporated by heating the
specimen in a tube in a stream of dry inert gas.
The gas is then passed into the cell.
Where the specimen is to be used directly without
dissolving in a suitable anhydrous solvent, an
appropriate quantity, accurately weighed, may be
introduced into the chamber directly.
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27. Viscosity
Rotational methods( apparent viscosity non
newtonian fluids & viscosity newtonian fluids)
1)Spindle viscometer
2)Concentric cylinder rheometer(cup and bob
rheometer)
3)Cone and plate rheometer
4)parallel plate rheometer
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32. Determine apparent viscosities by changing the
shear rate (or shear stress, if using a controlled
shear stress rheometer) over a range appropriate
to the use of the material under
test. From a series of such viscosity
measurements, the relationship between the
shear rate and the shear stress of a non-
Newtonian liquid can be obtained.
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34. some advantages of the parallel plate rheometer
include ease of sample loading
(especially tor very viscous liquids and soft
semisolids), and suitability for suspensions of
particulates.
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35. Dissolution
• USP has recommended: the vertical diffusion
cell (Franz diffusion cells);the Immersion cell
with USP apparatus 2;and USP apparatus 4 with
a special adapter cell for in vitro release testing
of semisolid dosage forms
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36. Vertical diffusion cell
Many vertical diffusion cell (VDC) systems are
composed of 6-cell units. Each VDC cell
assembly consists of two chambers (a
donor chamber and a receptor chamber)
separated by a membrane and held together by a
clamp, screw top, or other means.
The release rate experiment is carried out at 32
― 1 °, except in the case of vaginal drug
products for which thetemperature should be
37 + 1°. Usually a set of 6 cell assemblies are
operated together at one time
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37. Sampling generally is performed over a 4-6 h
time period, and the volume withdrawn is
replaced with stock receptor medium. To
achieve sink condition, the receptor medium
must have a high capacity to dissolve the drug,
and the drug concentration in the receptor
medium at the end of the test ideally should
be as low as possible.
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41. MODEL A
The thickness of the sample chamber normally is
1.5 mm. This thickness should be sized within
+10% of the specified thickness.
The glass support disk is used to occlude the
semisolid dosage form. A receptor cell mixer and
stirrer magnet are used as
the internal stirring mechanism.
MODELS B AND C
Classic styles of VDC are depicted in Figure 2 and
Figure 3 and illustrate minor design variations
among qualified models
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42. Immersion cell
The immersion cell can be used with USP Apparatus Dissolution
with vessel volumes that vary from 100 mL up to 4 L, but the 150-
or 200-mL vessels are the most commonly used. A flat-bottom
variation of the 150- or 200-mL vessel can be used to avoid the
issue of dead space under the cell when it is used in a round-
bottom vessel. If analysts are going to use a 150- or 200-mL vessel
with USP Apparatus 2, then the appropriate modifications must
be made, including holders for the small-volume vessels and
replacement of the standard paddle with the appropriate paddle.
It also may require repositioning of any automated sampling
device and/or manifold. The water bath or vessel heater should
be set to have the medium temperature at 32.0 ― 0.5° or 37.0 .
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Drug Release Rate Determination Using
Immersion Cell Apparatus
The cell consists of the following components
a retaining or lock ring that secures the membrane to the cell body
and ensures full contact with the sample; a washer that
provides a leakproof seal between membrane, retaining ring, and cell
body; the membrane (usually a synthetic membrane)
that should retain the sample in the sample compartment; and the
cell body that provides a variable depth reservoir for the
sample. Model A also has an adjustment plate that allows operators to
vary the volume of the reservoir within the cell body.
The plate can be placed at the appropriate height for each test and
can be completely removed to facilitate cleaning. An Oring
paired with the adjustment plate prevents leakage.

46. Uniformity in Containers
Carefully remove or cut off the bottom tube seal and
make a vertical cut from the bottom to the top of the
tube. Carefully cut the tube around the upper rim,
open the two flaps, and lay the flaps open to expose
the product.
Inspect the product visually for the presence of phase
separation, change in physical appearance and
texture, and other properties described in the product
test for Description. If there is no observable phase
separation or change in physical appearance
and texture, and if the product meets the Description
acceptance criteria, proceed as described in the
following sections. If the product exhibits phase
separation and/or change in physical appearance or
texture, the product fails the tube content
uniformity test.
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47. For multiple-dose products that contain 5 g or more
Procedure 1
1. Using a single tube, after visually inspecting the product, remove an
appropriate amount of product from the top, middle,
and bottom portions of the tube. The sample size should be sufficient for at
least one quantitative determination of
the active ingredient(s). Determine the amount of the active ingredient(s) in
each portion of the product using any appropriate
validated quantitative procedure, and evaluate the test results using Acceptance
criteria A.
2. If the product fails Acceptance criteria A, test three additional tubes from the
same batch following step 1 described above,
and evaluate all 12 test results using Acceptance criteria B.
Procedure 2
1. Using two tubes, after visually inspecting the product, remove an appropriate
amount of product from the top, middle,
and bottom portions of each tube. The sample size should be sufficient for at
least one quantitative determination of the
active ingredient(s). Determine the amount of the active ingredient(s) in each
portion of the tube using any appropriate
validated quantitative procedure, and evaluate the test results using Acceptance
criteria A.
2. If the product fails Acceptance criteria A, test two additional tubes from the
same batch following step 1 described above,
and evaluate all 12 test results using Acceptance criteria B.
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48. For multiple-dose products that contain less than 5 g of product
1. Test the top and bottom portions of two tubes using Procedure 7 or
Procedure 2 as described above. Evaluate the test
results using Acceptance criteria A.
2. If the product fails Acceptance criteria A, test two additional tubes
from the same batch following step 1 described above,
and evaluate all eight test results using Acceptance criteria B.
Tube (container) content uniformity test acceptance criteria: In
determining the relative standard deviation (RSD)
from multiple tubes, first determine the variance from the three
measurements for each tube and average across the tubes.
The RSD is calculated using this average variance.
Acceptance criteria A—All results are within the product assay range,
and the RSD is NMT 6% or as specified in the product
specification or in the compendial monograph. If the RSD is greater
than 6%, use Acceptance criteria B.
Acceptance criteria B—All results are within the product assay range,
and the RSD of the 12 assay results is NMT 6% or as
specified in the product specification or in the compendial
monograph.
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49. PRODUCTS PACKAGED IN CONTAINERS OTHER
THAN TUBES
For semisolid products packaged in a container
other than a tube when the sampling method
presented previously cannot
be used, other sampling methods are acceptable,
such as the following one described for a jar.
1. Select a suitable syringe of sufficient length to
extend to the bottom of the container.
2. Remove and set aside the syringe plunger, and
cut off the bottom of the syringe barrel. Sampling
should take place from a location to the left/right
of the mid-line of the jar surface to preserve an
undisturbed region on the other side for any
additional investigation
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51. 3. Slowly push the syringe barrel into the container until it
reaches the bottom. Then, twist the syringe barrel containing
the
sample core, and remove the syringe from the container.
4. Insert the syringe plunger into the barrel, and carefully
extrude the sample core onto a clean surface in three equal
portions
to represent the top, middle, and bottom portions of the
container.
5. Remove an appropriate sample representative of the
middle section of the top, middle, and bottom portions of the
container
samples, and test according to the instructions outlined in
Products Packaged in Tubes.
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