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
We are developing a colon-targeted dosage form containing a BCS II drug substance. What should be taken into consideration in the development of the dissolution test?
A
When the dosage form is targeted to release the drug at the colon, the dissolution test has three stages: (1) acid stage, where not more than 10% of the label claim should be released; (2) buffer stage pH 6.8, where, in most cases, not more than 10% of the label claim should be released; and (3) buffer stage at about pH 7.2, where most of the drug should be released. The medium pH in the third stage is going to depend on the formulation and the release mechanism. For the drug to be absorbed, it needs to be in solution. Therefore, BCS II drug substances should be formulated so that solubilization of the drug substance is promoted at the site of absorption. The book Drug Delivery and Targeting, Hillery AM, Lloyd AW, Swarbrick J, Taylor & Francis, 2001, discusses the characteristics of the most used routes of administration and what is needed for drug substances to be absorbed at these specific sites. The volume of medium should be determined considering the sink condition for the highest dose of the product that is going to be marketed.
Q
Regarding the measurement of dissolved gas or oxygen in dissolution media, is the temperature of the pre- and postdegassing media critical? What is the most widely accepted method, to measure dissolved gas pressure or dissolved oxygen?
A
The solubility of a gas in water is a function of tempera- ture. Thus, a determination of the degree of saturation will be temperature-dependent. However, dissolved oxygen meters can output the oxygen concentration in mg/L The dissolved oxygen concentration of degassed medium is expected to increase on standing and during the dissolution test. For the performance verification test of dissolution apparatus, the recommendation by USP is to start with a medium that has been degassed to about
6 mg/L, and that is at about 37 °C. For dissolution media that have been degassed without using inert gas sparging, the dissolved oxygen content in mg/L is a good indication of total dissolved gas. Please keep in mind that not all dosage forms will have dissolution profiles that are affected by the gases present in the medium. It is going to be case-by-case.
Q
We are developing an immediate-release tablet that contains an active pharmaceutical ingredient(API) that is insoluble in 0.1 N hydrochloric acid, but the official dissolution test uses this acid as dissolution medium. If the API is not soluble in this medium, how can we evaluate the drug release?
A
See the answer to the first question above. When you are developing a dissolution test, you need to consider the physicochemical characteristics of the drug substance; the release mechanism of the dosage form; the components of the formulation, their function at the amount that is being used; and the site of absorption. For the drug substance to be absorbed, it needs to be in solution. If the product is an immediate-release dosage form, most of its absorption will happen in the small intestine. That means that the drug should be dissolved either in the stomach or small intestine (duodemnum, jejunum, ileum). If the drug substance has poor solubility in these regions, the product needs to be formulated so that the solubility of the drug substance is enhanced/facilitated. Therefore, you need to consider the components of the formulation and how they are going to perform. Understand that it is possible to have a dissolution test with a medium where the drug substance has low solubility.
Q
What is the best way to document dissolution results, as a mean of the six results or as a range from lower results to higher ones?
A
Dissolution results can give you a tremendous amount of information depending on how you treat them. The mean value gives a summary of performance over the sample units, and a listing of individual results gives more detail. The best way to evaluate how a product is performing is to run a dissolution profile (amount of drug substance release versus time). At each time point in the profile, the individual results, the average of the results, and the standard deviation should be noted. In most cases, the standard deviation is higher at the earlier time points. Several statistical tools such as ANOVA can be used to evaluate the dissolution results. The calculation gives additional useful information about the probability of the product going to Stage 2 and Stage 3 (see the Acceptance Tables in the USP general chapter <711> Dissolution).
Q
We are developing a chewable tablet. The pH of saliva is between 6.2 and 7.4. Should we use dissolution media within this pH range to evaluate drug release from this product?
A
Chewable tablets are used to facilitate swallowing, mainly for special populations like children and geriatric, or when the tablet is too big. The drug substances formulated in chewable tablets are going to be absorbed in the gastrointestinal tract and not in the mouth. The selection of the dissolution medium for chewable tablets should consider the body region where most of the absorption is going to take place and not the conditions in the mouth. The dissolution test should be carried out with the intact tablet and not crushing or powdering it to simulate the worst-case scenario where the patient swallows the tablet without chewing it.
Q
I work at a company that manufactures dosage forms for clinical trials. We are frequently asked to develop discriminating dissolution tests, but I do not have any clinical data of failed batches to assess the discriminatory power of the test. We develop dissolution procedures that promote drug release gradually over 45 min (for immediate release) or over 24 h (for modified release), but we do not have any evidence that these dissolution methods can distinguish between batches that are significantly different in terms of tablet constituents, in vivo release profile, and therapeutic effect. What do we need to do to have a meaningful discriminative dissolution medium in cases like this?
A
The only way to know if you have a discriminating dissolution test is to challenge it with formulations that vary the critical quality attributes. If you do not have access to these formulations, then you are limited. However, if you make the dissolution profile slow enough, chances are that the dissolution test will give you some discrimination. In a Quality by Design (QbD) environment, the design of experiments (DOE) is a powerful tool.You should try to obtain pilot formulations that could be used in the DOE for a better evaluation of the discrimination power of the dissolution test.
Q
Can the procedure described in the USP Performance Verification Test, Apparatus 1 and 2, be used for the evaluation of 2-L vessels?
A
The volume of medium used for the PVT of Apparatus 1 and 2 is 500 mL. The dimensions of the 2-L vessel are identical to those for the 1-L vessel except for the height. Therefore, a volume of 500 mL of medium could be used in the 2-L vessel, and the procedure performed to give equivalent values for the 2-L vessel as for the 1-L vessels. Sample withdrawal and temperature measurements might present some challenges because of the greater distance to the sampling zone, but those challenges can be overcome.