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9
Quality control of suppositories
QUALITY CONTROL procedures listed in the US drug substances or excipients, or in the prepara-
Pharmacopeia (USP30-NF25) for manufactured tion of drug products. They are not completely re-
suppositories include identification, assay, and, moved during processing but should be removed
in some cases, water content, residual solvent, to the extent that is possible and reasonable.
dissolution, and content uniformity:
r Identification: Identification tests are com- Stability considerations in dispensing practice
for suppositories also include observations on
monly used for the identification and confirma- excessive softening and oil stains on packaging.
tion of official articles. Compounded suppositories can be checked for
r Assay: Assay and test procedures are used to calculations of theoretical and actual weight and
determine compliance with the pharmacopeial weight variation, color, hardness, surface texture,
standards of identity, strength, quality, and pu- and overall appearance.
rity. Chromatographic methods are commonly Suppository quality control includes physi-
used for detection and quantitation. cal and chemical aspects of the product (Box
r Dissolution: Dissolution testing is used to de- 9.1). Physical analysis includes visual examina-
tion (physical appearance), uniformity of weight,
termine compliance with the dissolution require- uniformity of texture, melting point, liquefac-
ments, if present in the individual monographs. tion time, melting and solidification time, and
The test measures the rate and extent of a drug mechanical strength. Chemical testing includes
dissolving in a defined medium under defined analysis of the activity and dissolution testing.
conditions. The uniformity of texture can be assessed by
r Water: As many pharmacopeial articles either sectioning a suppository longitudinally and lat-
are hydrates or contain water in adsorbed form, erally, and ensuring that each section presents a
the determination of water content may be im- smooth, uniform surface.
portant in demonstrating compliance with Phar- A list of official USP suppositories and required
macopeial standards. Three methods are com- quality tests is given in Table 9.1.
monly used: Method I is a titrimetric method,
Method II is an azeotropic method, and Method
III is a gravimetric method.
Physical analysis
r Content uniformity: Content uniformity is re-
quired in some monographs to ensure the consis-
tency of dosage units. These dosage units should
Visual examination
have a drug substance content within a narrow
Color and the surface characteristics of the sup-
range around the label claim. Weight variation
pository are relatively easy to assess. It is impor-
and content uniformity testing involving groups
tant to check for the absence of fissuring, pitting,
and individual dosage units are used.
fat blooming, exudation, sedimentation, and the
r Residual solvents: For pharmacopeial purposes, migration of the active ingredients. Suppositories
these are defined as organic volatile chemicals can be observed as an intact unit and also by
that are used or produced in the manufacture of splitting them longitudinally.
139
Royal Pharmaceutical Society of Great Britain September 16, 2007 23:30
140 Suppositories
Box 9.1 Example standard operating procedure: performing physical quality assessment of compounded
suppositories
I. Purpose – The purpose of this procedure is to 4 Remove the beaker contents, empty and dry the
provide a method of documenting uniformity between beaker.
batches and physical quality assessment tests of and
5 Place the dosage form (and the weight if used) into
observations on suppositories.
the beaker.
II. Materials, balance, graduates, beaker, weights.
6 Measure the same volume of water as in step 2 into
III. Procedures – Conduct the appropriate tests and a graduate.
record the results/observations on the Physical Quality
7 Pour the water into the beaker only to the mark
Assessment Form for Suppositories (Box 9.2).
from step 3. (Note: Do quickly before the dosage form
dissolves.)
A. Weight – Accurately weigh the product on a
balance. 8 Measure the volume of water remaining in the
beaker.
B. Specific gravity – To calculate the specific gravity,
Calculations:
one must know the weight and volume of the product.
Now that the weight and volume of the product
Record the weight of the individual dosage form or
are obtained, the specific gravity can be cal-
a strip/package of the dosage forms (tared weight).
culated by dividing the weight (grams) by the
To determine the volume of water displaced, do the
volume (in milliliters).
following:
C. Active drug assay results – As appropriate, have
Single unit:
representative samples of the product assayed for
1 Place 5.0 mL of water in a 10 mL graduate.
active drug content by a contract analytical laboratory.
2 Add the dosage form and read the water level. Stability can be assessed by storing the product at room,
refrigerated and/or frozen temperatures and having the
3 Subtract 5.0 mL from the level in step 2 to determine
assay repeated on the stored samples.
the volume of water occupied by the dosage form.
D. Color of product – It may be advisable to use a color
4 If the dosage form floats, place a weight attached
chart for determining the actual color of the product.
to a paper clip in the graduate prior to adding the
water to the 5.0 mL mark. Then, wrap one end of the E. Evaluate clarity by visual inspection.
paper clip around the dosage form to hold it below the
F. Texture of surface – Observe the product to deter-
water surface and place it in the graduate. Proceed as in
mine smoothness of the surface.
step 3.
Multiple unit packages (suppository strip): G. Appearance (dry, oily/moist) – Determine whether
1 Place the empty package in a beaker that will hold the product appears dry or oily/moist.
it with minimal extra space. H. Feel (tacky, plastic, elastic) – Touch the product to
2 Add an exact known quantity of water to cover the determine whether it is sticky (tacky) or hard (plastic) or
product. It may be necessary to add a weight to the bounces back (elastic).
package; this same weight should be used for the actual I. Melting test (for fatty acid, cocoa butter and oil-
product. based products):
3 With a fine-line marker and with the beaker setting
on a level surface, mark the water level on the outside
of the beaker.
Royal Pharmaceutical Society of Great Britain September 16, 2007 23:30
1 Heat a 200 mL beaker of water to 37◦ C on a 2 After 30 minutes, record your observations as yes,
magnetic stirring unit set at about 50 rpm. no or partially dissolved on the scale provided.
142 Suppositories
Product: Date:
shortcoming is the use of limited data to de- must be used because if the suppository is melted
scribe a continuous, complex melting process before a measurement is made, the supposi-
occurring in successive steps involving multiple tory constituents may be transformed into a
components, including various molecular weight metastable state.
triglycerides, polymers, or other ingredients. The melting test consists of placing a suppos-
The methods used are similar in principle itory on the surface of water thermostatically
but include different steps and techniques. In controlled at 37◦ C and verifying the complete
general they include the set-up of the equipment, melting of the suppository in a few minutes. This
placement of the suppository dosage unit in the is not so much a measurement as an evaluation.
apparatus, followed by the application of heat
and observation for a change in the system, such
as melting or movement. The results obtained
Melting point determination
using different methods do not always agree, so
it is important to use a consistent method. The use of a U-shaped capillary tube to determine
In general, the melting point should be equal melting point provides precise information for
to or less than 37◦ C. A non-destructive method excipient control and consistency in production
Royal Pharmaceutical Society of Great Britain September 16, 2007 23:30
Content Residual
Monograph Identification Assay Dissolution Water uniformity solvents
Acetaminophen x x – – – x
Aminophyllinea x x – – –
Aspirinb x x – – –
Bisacodyl x x – – –
Chlorpromazinec x x – – –
Ergotamine tartrate and caffeine x x – – – x
Glycerin x x – x – x
Indometacin x x x – x x
Miconazole nitrate x x – – – x
Morphine sulfate – x – – x x
Nystatin – x – x –
Oxymorphone hydrochloride x x – – – x
Prochlorperazine x x – – –
Progesterone – x – – x x
Promethazine hydrochloride x x – – –
Thiethylperazine maleate x x – – x
for those suppositories containing soluble active as amorphous to crystalline transitions. They also
principles. This method is not suitable when the demonstrated a hardening of the suppository ma-
suppositories have a high powder content, which terials over periods of time as short as six weeks,
prevents the fat from sliding inside the capillary using a modified Krowczynski softening time test
tube to give the end-point determination. and differential scanning calorimetry on freshly
When there are more numerous controls, and solidified, incrementally aged, and equilibrated
where studies with a greater precision can be samples. They also demonstrated that plasticizers
undertaken, an apparatus can be used consisting inhibited this hardening phenomenon.1
of a microscope, a heated deck, and a recorder.
This provides for a more detailed observation and
recording of the melting process.
The melting point can also be determined Liquefaction time
by placing a small-diameter wire into the mold
containing the suppository melt before the form Liquefaction testing provides information on
solidifies. The form is then immersed in water, the behavior of a suppository when subjected
held by the wire, and the temperature of the to a maximum temperature of 37◦ C. The test
liquid is raised slowly (about 1◦ C every 2–3 commonly used is Krowczynski’s method (see
minutes) until the suppository slips off the wire; below), which measures the time required for a
this is the melting point of the suppository. suppository to liquefy under pressures similar to
In a study by Coben and Lordi, the changes in those found in the rectum (approximately 30 g)
the melting range of several semi-synthetic sup- in the presence of water at 37◦ C. In general,
pository bases over time were investigated. Using liquefaction should take no longer than about
X-ray diffraction they characterized the changes 30 minutes.
Royal Pharmaceutical Society of Great Britain September 16, 2007 23:30
144 Suppositories
Elevating mechanism 6
Thermometer
Ring agitator 1 or —
1 C scale)
(—
n m
guide Rubber
80 mm
rise: 1 C per minute
Ring agitator
Asbestos plate
covered stand
protected from drafts
Bunsen pilot
flame φ 1,5 Int.
146 Suppositories
Thermometer
internal accurate to
within 0.1°C
30a
17a
161
125
25a
33
18a
2a
5a
Suppository
B A C
KROWCZYNSKI Water at 37 °C
APPARATUS
COMPLETE
ASSEMBLY
leading to different results obtained using dif- temperature in this phase is the solidification
ferent methods. The solidification temperature temperature.
is defined as the highest temperature occurring
during the solidification of a supercooled li-
quid. Various methods are available to measure Mechanical strength/crushing test
it, including Shukoff’s method,4 in which the
liquid is shaken in an evacuated flask until Suppositories can be classified as brittle or elastic
turbid and the temperature noted at which by evaluating the mechanical force required to
a transitory rise in temperature occurs during break them. Tests are used that measure the
cooling. mass (in kilograms) that a suppository can bear
The European Pharmacopoeia also describes without breaking. A good result is at least 1.8–
a procedure that involves heating the material, 2 kg pressure. In the example laboratory set-up
then allowing it to cool slowly while stirring. The shown in Figure 9.7, the suppository is positioned
temperature is recorded at 1 minute intervals. in an upright position and increasing weights
The cooling curve normally passes through a are placed on it until it loses its structure and
minimum, which indicates a supercooled melt. collapses. The purpose of the test is to verify that
Heat is liberated during crystallization and the the suppository can be transported under normal
temperature–time curve rises. The maximum conditions, and administered to the patient.5
Royal Pharmaceutical Society of Great Britain September 16, 2007 23:30
50
22
30
260
Cellophane
tube
30
Chemical testing
Dissolution testing
148 Suppositories
Paddle and
flask as defined
for Apparatus 2
Paddle
Disk 25 cm
Eccentricity
USP/NF: no significant wobble;
BP: no perceptible wobble
Sampling point
USP/NF: midway from top of
basket to top of fluid and no
closer than 1 cm to side of flask;
BP: halfway between basket
and side at middle of basket
A Flask
USP/NF: cylindrical with spherical bottom,
16–17.5 cm high, inside
diameter 10–10.5 cm, plastic or glass
Basket
Basket position
USP/NF: 25 ±0.2 cm; BP: 2.0 ±0.2 cm
Pump
C
A
37°C from attached to A attached to B
water bath pH meter
Na+ electrode
DIALYSIS
to
APPARATUS SECONDARY
water bath
D to VESSEL
B Apparatus
attached
to D
150 Suppositories
1
2
4
2
5
6
(a) (b)
Figure 9.11 Dissolution apparatus using the continuous flow method: (a) 1 – schematic drawing with the cell in the upper
middle of the diagram; 2 – tubing for moving the dissolution fluid; 3 – constant temperature bath; 4 – pump; 5 – receiver
flask for dissolution fluid; 6 – constant temperature bath; (b) continuous flow cell; 1 – beads; 2 – suppository being tested;
3 – filter (glass filter) to retain the beads.
from those without and produce the fastest to the drug partitioning between the melted
dissolution rates of paracetamol. The presence lipophilic base and the receptor fluid. This may
of the surfactant makes the suppository more result in a distribution equilibrium between the
sensitive to the differences in the dissolution phases as opposed to complete dissolution. In
techniques.6 these cases, sink conditions are essential in order
The flow-through method was slower, possibly to simulate the in vivo situation. In this situation
as a result of the delayed spreading of the melted membranes provide a more elegant way to obtain
mass in the dissolution cell. The subsequent con- a filtrate for immediate assay; however, because
tact area with the dissolution fluid is smaller than this poses an artificial condition, it is not gen-
that achieved with either the paddle method or erally recommended. Recommended equipment
the basket method.6 for lipophilic suppositories, therefore, includes a
In a series of workshops held under the modified basket method, a paddle method with
auspices of the Fédération International Phar- a wired screen and a sinker, and a modified
maceutique (FIP) and co-sponsored by the Royal flow-through cell with a specific dual-chamber
Pharmaceutical Society, the Bundesverband der suppository cell. The flow cell tends to generate
Pharmazeutischen Industrie, Colloquium Phar- more variability in the data due to the behavior
maceuticum, the American Association of Phar- of the suppository within the cell, especially in
maceutical Scientists, and the US Food and formulations that contain spreading agents. In
Drug Administration, it was concluded that these difficult situations, the membrane method
hydrophilic suppositories that release the drug may be preferable.7
by dissolving in the rectal fluids can be eval- It is evident that no single method of dis-
uated by the basket, paddle, or flow-through solution testing is suitable for all the various
cell methods. Lipophilic suppositories, on the suppository formulations and types of suppos-
other hand, release the drug after melting in itories. However, from the methods available,
the rectal cavity and are significantly affected by the authors concluded that a method can gen-
rectal temperature. After determining the proper erally be selected that will be adequate. Even
temperature to use, consideration must be given though it is difficult to make a recommendation,
Royal Pharmaceutical Society of Great Britain September 16, 2007 23:30
one might consider starting with the basket the Mühlemann tester and a laboratory-designed
or paddle method for hydrophilic suppositories membrane-diffusion cell. The values for the
and the modified flow-through cell for lipophilic dissolution rates were faster than the perme-
suppositories.7 ation rates, as would be anticipated. There was
A bead-bed suppository dissolution appara- good correlation between the Mühlemann tester
tus was evaluated by measuring the release of and the laboratory-designed membrane-diffusion
benzocaine from various suppository vehicles. cell. Based on this study, the authors concluded
This proposed method using beads as the bed that it is possible to obtain standardized and auto-
and placing the suppository within the beads mated results that show good reproducibility.11
was designed to provide greater constancy of An investigation was conducted to determine
the exposed suppository area for dissolution. The the in vitro dissolution behavior of piroxicam
liquid passed through the bed at a constant rate. suppositories using the flow-through method,
Direct contact of the suppository was maintained conventional stirred vessel–USP paddle and bas-
with the dissolution medium, confining the sup- ket methods. The results indicate that the flow-
pository within the beads.8 through method seems useful for studying the
A study to determine the feasibility of using dissolution process of suppositories containing
the European Pharmacopeia flow-through cell for piroxicam, resulting in reproducible dissolution
dissolution testing of compounded rectal sup- data. The flow-through cell method gives more
positories containing indometacin or sodium di- rapid in vitro dissolution rates for piroxicam than
clofenac investigated various suppository bases. the USP paddle method, possibly due to the
The fastest and most repeatable release rates were steeper concentration gradient in the vicinity of
from the hydrophilic bases; the macrogols had the suppositories as well as a better ability to
more than 80% of the drug released within 60 thoroughly wet the suppositories. The USP basket
minutes. The lipophilic bases were somewhat method gave substantially slower dissolution
slower, showing that after 350 minutes, only rates than either of the other two methods.12,13
18.5–50% of the total amount was released, with Using a dissolution chamber apparatus for
somewhat non-reproducible results. This demon- suppositories introduced in the European Phar-
strates the slow and non-reproducible release macopoeia and the British Pharmacopoeia, one
when the lipophilic suppository base does not study of commercial paracetamol suppositories
melt. The authors concluded that the use of the found that the results obtained are clearly de-
test for formulations that do not melt is not pendent upon the temperature maintained in the
recommended.9 dissolution chamber. Complete melting of a sup-
One study using the paddle dissolution pository in the dissolution chamber was required
method on water- and fat-soluble indometacin for an appropriate dissolution of paracetamol in
suppositories for rectal administration in rats vitro. Associated tests were compared for rele-
determined that the choice of the membrane vance, including disintegration time, softening
is critical. When a cellulose or artificial sausage time, drop point, and particle size.14
membrane of cow protein was used, the amount The release rates of fluconazole in different
of indometacin released from fatty base suppos- types of suppository bases was studied using the
itories was higher than that from water-soluble USP dissolution apparatus I and the permeation
bases. But, the results were reversed when a was studied using Franz diffusion cells with rat
natural sausage membrane of pig colon was rectal membrane with normal saline as the recep-
used. Selection of the proper model system is tor medium. The different bases used included
important.10 hydrophilic (PEG), lipophilic (cocoa butter or
A comparison of different dissolution and Witepsol W45), and amphiphilic (Suppocire AP,
permeation methods was undertaken using dia- a polyglycolized glyceride). The results of the
phyllin, piroxicam, naproxen, and tenoxicam dissolution test concluded that dissolution of
commercial standard suppositories. Dissolution fluconazole from the bases, in decreasing order,
tests were conducted with the Desaga-type flow was PEG ⬎ Suppocire AP = Witepsol W45 ⬎ cocoa
cell. Permeation studies were conducted using butter. The permeation studies showed Suppocire
Royal Pharmaceutical Society of Great Britain September 16, 2007 23:30
152 Suppositories
AP ⬎ PEG = Witepsol W45 ⬎ cocoa butter. It 1 unit of the 30 is outside the range of 85.0%
was mentioned that the increased permeation to 115.0% of label claim, and no unit is outside
characteristics seen with the Suppocire AP base the range of 75.0% to 125.0% of label claim and
are probably due to an alteration of the mem- the RSD of the 30 dosage units does not exceed
brane characteristics because of the surface active 7.8%.
properties of the base.15 Limit B (if the average of the limits specified in
In another study a case was presented for two the potency definition in the individual mono-
rotating flask methods (simple and compartmen- graph is greater than 100.0 percent).
tal) for evaluating the liberation of drugs from If the average value of the dosage units tested
is 100.0 percent or less, the requirements are as
commercially available acetaminophen supposi-
in Limit A.
tories. The authors compared numerous suppos-
If the average value of the dosage units tested
itory test methods but decried their complicated
is greater than or equal to the average of the
construction and difficulty in handling. They
limits specified in the potency definition in the
concluded that the two rotating flask methods individual monograph, the requirements are as
correlated well with each other and had relevant specified under Limit A, except that the words
characteristics and bioavailability.16 “label claim” are replaced by the words “label
claim multiplied by the average of the limits spec-
ified in the potency definition in the monograph
Content uniformity testing divided by 100.
If the average value of the dosage units tested
is between 100 percent and the average of the
In order to ensure content uniformity, individ- limits specified in the potency definition in the
ual suppositories must be analyzed to provide individual monograph, the requirements are as
information on dose-to-dose uniformity. Testing specified under Limit A, except that the words
is based on the assay of the individual content “label claim” are replaced by the words “label
of drug substance(s) in a number of individual claim multiplied by the average value of the
dosage units to determine whether the individual dosage units tested (expressed as a percent of
content is within the limits set. “Acceptance label claim) divided by 100 (p. 383).
value calculations are not required for supposi-
tories. Assay 10 units individually as directed in
Content uniformity is important not only be-
the Assay in the individual monograph, unless
tween suppositories, but also within supposito-
otherwise specified in the Procedure for content
ries in the event that a suppository is halved
uniformity” (ref. 17, p. 383).
for administration. A method of determining
The USP 30 “Criteria”17 for suppositories states
the distribution of paracetamol in suppositories
the following:
using differential scanning calorimetry has been
reported. In this study, samples of 2.5–4.0 mg
Limit A (if the average of the limits specified were carefully removed from the tip, middle,
in the potency definition in the individual
and base sections of individual paracetamol
monograph is 100.0% or less) – Unless otherwise
suppositories using a stainless steel scalpel. The
specified in the individual monograph, the re-
contents of paracetamol in the suppositories were
quirements for dosage uniformity are met if the
determined by differential scanning calorimetry
amount of the drug substance in each of the 10
and ultraviolet spectrophotometry. The results
dosage units as determined from the Content
Uniformity method lies within the range of obtained were 10.1 ± 0.2%, 10.1 ± 0.2%, and
85.0% to 115.0% of the label claim, and the RSD 10.3 ± 0.2% w/w paracetamol, indicating that the
is less than or equal to 6.0%. paracetamol was uniformly distributed through-
If 1 unit is outside the range of 85.0% to out the suppositories.18
115.0% of label claim, and no unit is outside the One study reported difficulty in obtain-
range of 75.0% to 125.0% of label claim, or if the ing content uniformity between dispensatory-
relative standard deviation is greater than 6.0%, prepared rectal suppositories when sampling
or if both conditions prevail, test 20 additional numbers were only 10% of a batch of 300 (N
units. The requirements are met if not more than = 30). This was solved by increasing the number
Royal Pharmaceutical Society of Great Britain September 16, 2007 23:30
of suppositories tested to 15% (N = 45) of the and where samples are obtained. Here we are con-
total batch prepared.19 cerned with the general homogeneous nature of
Content uniformity tests can be used to mixed products in a single system or unity, or in a
optimize production techniques and sampling single operation being used for the manufacture
methods. In one study a sampling plan was de- of suppositories under constant modalities.
veloped, combining practicality for the consumer Active drug analysis is important for batch-
and a satisfactory discrimination between “good” to-batch uniformity and can also be used for
and “bad” batches. Samples of 50 suppositories within-batch production control. The analysis
obtained from a year’s production of 42 batches of active drugs in suppositories presents some
were studied. There was no difference between interesting and sometimes difficult problems due
the weights of the suppositories obtained during to the matrix in which they are contained, such
the production process. The intent was to deter- as fatty acids and long-chain polymers. Once
mine the variation in content as there was no uni- assay methods have been developed, they can be
form standard. At the time of this study (1970), used to also determine content uniformity and
the German and Russian pharmacopeias allowed dissolution testing parameters.
weight variations of rectal suppositories of within
±5% of the average weight. The Pharmacopoeia
Nordica allowed weight deviation up to ±10% of
the average weight for 90% of the suppositories, Sampling and sample preparation
provided that the variations do not exceed ±20%.
The International (1967), NF XII, BP (1963), Ital- In general, the analytical methods involved
ian VII, Austrian IX, Gallica VIII and Japanese VII require sample preparation prior to using an
pharmacopeias gave no specification for weight instrumental method technique. Sample prepa-
uniformity of suppositories.20 ration involves the preparation of a suitable and
uniform sample composite and the extraction of
the drug from the excipients.
For manufactured suppositories, preparation
Conductivity
of a uniform sample may require a minimum of
five to 30 individual doses which are weighed
Siegmund and Leuenberger studied the conduc- and combined together, such as by melting in
tivity of binary mixtures of different volume to a beaker. From this composite, the required
volume ratios of liquid PEG 200 and solid PEG quantity of sample is removed for analysis.
6000 in an attempt to relate this to dissolution The quantities for sampling are usually a
rate processes. The conductivity was measured minimum of 10–15 suppositories. The samples
using a specially designed cell, which could be are taken from the first ten molds, from the
filled with the sample to be analyzed. The results beginning, from the middle of the manufacturing
were analyzed using the percolation theory and and finally from the last ten molds, and are
its relation to the dissolution rate of binary placed in impervious packing, preferably made
mixtures. They demonstrated that the conduc- of glass, and then labeled. The samples can also
tivity and the dissolution rate process can be be taken from directly packaged suppositories.
successfully modeled by the basic equation of Special care must be taken when labeling the
percolation theory and that both processes can sample receptacles, making sure that the date
be correlated.21,22 when the sample was taken, and the batch
number are included.
Sample preparation techniques may require
extraction, heating, the addition of electrolytes
Chemical testing procedures
to the aqueous phase (salting out), modification
of the surface tension by addition of silicones,
Prior to chemical testing, the size of the manu- ricinoleate, octylic alcohol or others, centrifu-
facturing batch must be defined. This may invoke gation, acidification (particularly anionic type
specific requirements on sample size and when emulsion of the soap type) or the addition of an
Royal Pharmaceutical Society of Great Britain September 16, 2007 23:30
154 Suppositories
organic solvent. Often it is necessary to combine the water 15 minutes before introducing the
the techniques described above. suppository to be tested; and the third is used
to sample the dialysis water at regular intervals.
These dialysis samples are then quantitatively
Extraction analyzed for the active principle that has diffused
from the suppository.
The method used to extract the active drug The test liquid (350 mL), from which the
from the sample varies depending upon the samples are obtained, with a pH of 7.38, is used
physicochemical characteristics of the drug and in each test. Samples to be analyzed are taken at
the vehicle. Many extraction procedures require 30, 60, 90, 120, 150, 180, 210, and 240 minutes.
partitioning into an aqueous medium after mix- The composition of the test liquid is as follows:
ing with either hexane, pentane, chloroform, Na2 HPO4 .2H2 O (9.50 g), NaH2 PO4 .2H2 O (2.08 g),
ether, or another suitable organic solvent. In NaCl (4.60 g), polyvinylpyrrolidone (35.0 g),
some methods, multiple extractions and back purified water to 1000 mL.
extractions may be required.
Dialysis
Extraction by water at 37◦ C method
A modification of the dialysis membrane method
One suppository per test is placed in a tube
for drug release from suppositories was used
containing 10 mL of water at 37◦ C. After stirring
to analyze dissolution from 50 mg indometacin
in a constant temperature water bath, the tubes
suppositories. The system consisted of a dialysis
are withdrawn at 10-minute intervals and imme-
membrane (17 cm long, 28 mm wide), suspended
diately placed in an ice bath to solidify the melted
in 1000 mL of 50 mM phosphate buffer main-
excipient. The concentration of the active drug in
tained at 37◦ C. This technique also uses a clamp
the supernatant liquid is then determined.
to bind the ends of the tubing rather than thread
(which tends to wrinkle the tubing at the ends).
Extraction by dialysis across a cellophane The results using the apparatus allowed cor-
membrane relation of the release rate with in vivo data
(AUC, Cmax and T max in rabbits). In this method,
Several methods studying the diffusion of active any water remaining in the dialysis tubing after
principles originating from melted supposito- hydration resulted in a decrease in the rate of
ries at a temperature near 37◦ C across a semi- drug release due to lost sample.26
permeable membrane have been used.23–25 Example set-ups are shown in Figure 9.12.
Other methods
Preparation for analysis
There is another method that deserves close
attention as it seems to give excellent corre- Once the sample has been extracted, the next
lation with in vivo absorption results obtained step is the analytical method. Analytical meth-
with different suppository formulas, notably with ods commonly include high-performance liquid
thiazinamium and indometacin. The apparatus chromatography (HPLC), gas chromatography,
consists of a cylindrical dialysis cell placed in a and spectroscopy. Ideally, all methods should be
water bath at 37◦ C. The water bath has a circula- capable of indicating stability.
tion of liquid assured by thermostatic control and In selecting the analytical method, important
a water pump. The dialysis cell has three orifices: factors to be evaluated include (1) the solubility
the first holds a precision thermometer used to characteristics of the active ingredients, (2) par-
control the temperature of the dialysis liquid; ticle fineness, (3) the hydrophilic or lipophilic
the second holds a cellophane gut (diameter character of the excipients, (4) the ability to
18 mm, thickness of 25 µm), which is placed in spread on the rectal mucous membrane, (5) the
Royal Pharmaceutical Society of Great Britain September 16, 2007 23:30
Dialysis cooling
lipophilicity of the compounds was assessed by
the partition coefficients ClogP (calculated log
55 mm
156 Suppositories
In another study, methods were developed for Some problems associated with aging include
investigating the release of carbon dioxide from the following:
effervescent suppositories containing sodium bi-
r An odor may emanate from suppositories with
carbonate and anhydrous sodium dihydrogen
phosphate for the purposes of formulation devel- vegetable extracts due to fungal contamina-
opment and quality control during production. tion.
r Suppositories with some dyes may discolor
Method 1 was conducted without stirring and
method 2 was with stirring; the evolution of due to oxidation of the dyes.
r The shape of some suppositories may be al-
carbon dioxide was measured using a gas bu-
rette. Three lots of commercial suppositories were tered during storage at incorrect temperatures,
used. Using method 1, only 60% of the carbon especially if they contain essential oils.
r Suppositories containing vegetable extracts or
dioxide was released in the medium without
polysorbate 80; since no stirring was involved, caffeine base may exhibit whitening on the
this was a “native” release profile. In method 2, surface.
r Suppositories containing camphor, menthol,
100% was released containing 1% polysorbate 80
with comparatively low standard deviations. The or other volatile substances that may be lost
authors concluded that method 1 would be most due to vaporization over time may lose weight
beneficial for comparing the effects of various during storage.
r Other aging phenomena, such as hardening,
factors, such as additives and melting points, on
the release profiles of carbon dioxide from the softening, bloom, mottling, discoloration and
suppositories; however, this method would not cracking may occur over time depending upon
be practical for quality control as only about 60% the composition of the suppositories and stor-
of the carbon dioxide was released. Method 2, age conditions.
on the other hand, would be useful because of
its complete release and low standard deviations.
These methods are applicable, therefore, to early
and late formulation studies of effervescent sup- References
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