William Brown and Margareth Marques
The following questions
have been submitted by readers of Dissolution Technologies. Margareth
Marques, Ph. D. and Will Brown, United States Phamacopeia, authored
responses to each of the questions.
*Note: These are opinions and interpretations of the authors,
and are not necessarily the official viewpoints of the USP
Email for correspondence:
web@usp.org
Q
Should the qualification of a dissolution apparatus using the USP reference
standard tablets be performed before or after the calibration of the dissolution tester?
A
The mechanical calibration of the test assembly is performed before the performance
verification test (PVT) that uses the USP reference standard tablets.
Q
Do the calibration and performance verification of a dissolution tester
complement each other? For example, if one of the calibration parameters (such as wobbling)
is slightly out of specification, but the performance test using the USP Reference Tablets
meets the criteria, can we assume that the dissolu- tion equipment is in good condition to
carry out the dissolution testing?
A
Mechanical calibration and PVT are complementary tests. Mechanical calibration provides a
qualification of the operation of the test assembly, confirming that the operating
parameters and measurements of the individual parts of the assembly are within the
allowed tolerances. If any mechanical calibration measurement is out of specifi- cation,
the test assembly is not suitable for dissolution testing. The PVT demonstrates that
dissolution results obtained by the test assembly are acceptably similar to results
from other mechanically calibrated test assemblies. Successful completion of both
procedures is necessary to verify that the test assembly is suitable for dissolution
testing. While the attainment of satisfactory results for the PVT with one of the
mechanical calibration measurements "slightly out of specification" is conceivable,
it would not be adequate justification to proceed without repair of the failing
measurement (and repeat of the PVT).
Q
Most of the dissolution tests for immediate- release dosage forms have tolerances
in the range of NLT 70% to NLT 80%. Is there any upper limit for the test? Sometimes we
see results up to 122%. What are the possible reasons for extremely high percentages dissolved?
A
There are no upper limits for dissolution results, but the results are related to
the drug content and the uniformity of dose for a particular product. One dosage
form unit is tested at a time; the behavior of this unit during the dissolution
test is going to reflect the variability of the manufacturing process. In a process
under control, the
uniformity of dose is, in most cases, from 85% to 115% of the product label claim.
If the manufacturing process is under control, you should see very few results above
100% of the product label claim. If observed, results above 115% should be few and
balanced with results within the 85-115% range. Possible causes for very high dissolution
results are deviations in the manufacturing process, interference of the placebo
composition in the quantita- tive step of the dissolution test, inappropriate filter
and filtering process of the dissolution, and errors in the sampling process. If very
high or consistently high dissolution results are found, an investigation should be
conducted to identify the possible reasons, both in the analytical lab as well as in
the manufacturing area.
Q
According to USP 33-NF 28, the performance verification test (PVT) for
USP Apparatus 1 and Apparatus 2 using USP Salicylic Acid Tablets RS is no longer
required. With the recall of USP 33, can we proceed with the use of USP Salicylic
Acid Tablets RS?
A
The removal of USP Salicylic Acid RS from the Apparatus Suitability section of the
USP General Chapter <711> Dissolution was official on 1 December 2009 in the Second
Supplement to USP 32-NF 27. Although the official text in the Second Supplement
would have been published again in USP 33-NF 28, it remains official in spite of
the recall of that publication. Currently, performance verification testing (PVT)
of USP Apparatus 1 and Apparatus 2 is done with USP Prednisone Tablets RS only.
Please note that
USP will change the approach for the procedure and interpretation of results for
these PVTs in the near future. An official statement on the subject can be found at
http://www.usp.org/pdf/EN/referenceStandards/2009DissolutionChange.pdf
Q
I was told that to determine the solubility of a drug substance for the
Biopharmaceutical Classification System (BCS), I should use four times the amount
stated in the WHO Essential Medicines listing. How should I do this solubility
determination?
A
For BCS purposes, the solubility is based on the highest dosage strength of the
immediate-release drug product that is going to be marketed. A drug substance is
consid- ered highly soluble when the highest dosage strength is soluble in 250 mL
or less of aqueous medium over the pH
range of 1-7.5. The solubility determination for BCS application should be carried
out at 37 ± 1 °C. Several papers in the literature explain the procedures
for this solubility determination.
Q
I am working with a drug substance that is soluble only above pH 6.8. To
determine the solubility for the Biopharmaceutical Classification of this drug,
I need to use at least three different solvents in the pH range of 1-7. How should
I select these three media if the drug substance is not soluble below pH 6.8?
A
The pH-solubility profile of the drug substance should be determined in aqueous media
with a pH in the range of 1-7.5. A sufficient number of pH conditions should
be evaluated to accurately define the pH-solubility profile. The number of pH conditions
for a solubility determination can be based on the ionization characteris- tics of the
drug substance. For example, when the pKa of a drug is in the range of 3-5, solubility
should be determined at pH = pKa,pH = pKa + 1,pH = pKa - 1,and at pH = 1 and pH = 7.5.
A minimum of three replicate determinations in each pH condition is recommended.
See the FDA Guidance for Industry, Waiver of In Vivo Bioavailability and Bioequivalence Studies for
Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System,
available at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070246.pdf